Gastric retentive pharmaceutical compositions for treatment and prevention of CNS disorders

ABSTRACT

The present disclosure is directed to methods and compositions for ameliorating, preventing and treating central nervous system (CNS) disorders. The invention aims to treat subjects suffering from, susceptible to, or diagnosed with CNS disorders, and in particular, to treating patients suffering from those disorders which are associated with neurotransmitter system dysfunction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/541,836, filed Aug. 14, 2009 which claims priority to U.S.Provisional Application No. 61/122,276, filed on Dec. 12, 2008, and U.S.Provisional Application No. 61/089,339, filed Aug. 15, 2008, thedisclosures of which are all incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present disclosure is directed to gastric retained pharmaceuticalcompositions and related methods useful in ameliorating, preventing andtreating central nervous system (CNS) disorders. The described inventionaims to treat patients suffering from, susceptible to, or diagnosed withCNS disorders, and in particular, to treating patients suffering fromthose disorders which are associated with neurotransmitter systemdysfunction, which include, for example, neurodegenerative diseasesincluding presenile dementia, senile dementia of the Alzheimer's type,and Parkinsonism including Parkinson's disease, and other CNS disordersincluding attention deficit disorder, schizophrenia and Tourette'ssyndrome.

BACKGROUND

CNS disorders are a type of neurological disorder. CNS disorders can bedrug induced, can be attributed to genetic predisposition, infection ortrauma, or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses,and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a cholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency and/or a serotonergic deficiency. CNS disorders of relativelycommon occurrence include presenile dementia (early onset Alzheimer'sdisease), senile dementia (dementia of the Alzheimer's type),Parkinsonism including Parkinson's disease, Huntington's chorea, tardivedyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety,dyslexia, schizophrenia and Tourette's syndrome.

Parkinson's disease (PD) is a debilitating neurodegenerative disease,presently of unknown etiology, characterized by tremors and muscularrigidity. A feature of the disease appears to involve the degenerativeof dopaminergic neurons (i.e., which secrete dopamine). One symptom ofthe disease has been observed to be a concomitant loss of nicotinicreceptors which are associated with such dopaminergic neurons, and whichare believed to modulate the process of dopamine secretion. See, Rinne,et al., Brain Res., Vol. 54, pp. 167-170 (1991) and Clark, et al., Br.J. Pharm., Vol. 85, pp. 827-835 (1985). It also has been proposed thatnicotine can ameliorate the symptoms of PD. See, Smith et al., Rev.Neurosci., Vol. 3(1), pp. 25-43 (1982).

The combination of levodopa and carbidopa in considered to be the mosteffective treatment for symptoms of Parkinson's disease (The MedicalLetter, 35:31-34), 1993). For subjects afflicted with and/or diagnosedwith Parkinson's disease, the benchmark treatment is typically oraladministration of a dosage form containing levodopa in combination withcarbidopa. Levodopa is a precursor of dopamine but unlike dopamine, isable to cross the blood brain barrier. However, while in the peripheralblood system and prior to crossing the blood brain barrier, levodopa isdecarboxylated into dopamine. Carbidopa inhibits the rapid peripheraldecarboxylation of levodopa into dopamine. The negates the need for highdoses of levodopa which would result in adverse events, i.e., sideeffects, in particular nausea, caused by the dopamine released into thecirculation from levodopa conversion in the intestinal mucosa and otherperipheral tissues. Currently, oral levodopa/carbidopa combination drugproducts on the market consist of immediate release tables, for example,Sinemet® and Atamet®, and extended release tables, for example, Sinemet®CR and generics. Carbidopa is also available as single-ingredienttablets for those patients who require additional carbidopa when takingthe combination tablets.

Immediate release levodopa/carbidopa tablets are administered three orfour times a day and the extended release product is administered two tothree times a day. Recently, an external pump that infuses levodopa andcarbidopa into the duodenum at a controlled rate through a surgicalopening in the stomach became available in Europe and Canada (Duodopa®,Solvay Pharmaceuticals, Germany).

It is know that exposure of affected neurons in Parkinson's disease toexogenous dopamine in a pulsatile fashion, such as in oraladministration of levodopa in immediate release form to Parkinson'spatients, eventually, in two to three years, leads to the development ofthe “on-off” phenomenon, i.e., mobility is improved for a couple ofhours after each dose, but rigidity and akinesia return at the end ofthe dosing interval. Dosing more frequently would improve this butdyskinesia, excessive and abnormal involuntary movement, would occurwhen levodopa level becomes high. It is also know that when levodopalevels are maintained constant by IV infusion at a constant rate, theon-off phenomena and dyskinesia are reduced. This is also mimicked bytaking subdivided daily oral doses frequently, such as every two hoursinstead of four or six hours. The later can in theory be realized in anoral extended release dosage forms. However, the unique oral absorptioncharacteristics of levodopa have present problems in achieving an oralextended/controlled release dosage form that delivers the drug at arelatively constant rate for an extended period of time to achieverelatively constant plasma levels of levodopa.

As levodopa is only absorbed in the proximal small intestine via anactive transport mechanism for aromatic amino acids, this limits theperformance of conventional oral controlled release dosage forms whichare rapidly emptied from the stomach into the intestine. If the durationof release is long compared to the transit time through the smallintestine, about 2 to 3 hours, most of the drug is not delivered to thesite of absorption in the proximal small intestine and is not absorbed.Hence, the duration of release in the small intestine has to berelatively short in order not to lose bioavailability.

Such is the case for SINEMET® CR, for which complete in vitro release(dissolution apparatus 1, paddle, pH 1) occurs in about 2.5 hours.Formulations with longer release durations resulted in lowerbioavailability of levodopa. Even so, SINEMET® CR bioavailability isonly 70-75% of the immediate release tablet SINEMET®. Administrationwith food increases the bioavailability substantially since gastricemptying is slowed. Despite FDA recommended dosing of the drug two tothree times a day, in actual clinical practice, some patients mayrequire administration of the drug four to six times a day due.

A duodenum infusion pump can deliver levodopa and carbidopa, at aconstant rate, directly to the intestinal site of absorption therebymitigating the above problems. But such therapy is neither convenient ininitiation (surgical insertion of infusion tubing) nor in maintenance(wound and device care).

Thus, there is a strong need in the art for pharmaceutical compositionsthat effectively and conveniently aide in the treatment and preventionof movement disorders, such as Parkinson's Disease, by providingextended/controlled release of levodopa and carbidopa at a relativelyconstant rate for an extended period of time to achieve relativelyconstant plasma levels. The present disclosure meets these needs, amongothers.

Additional embodiments of the present method, compositions, and the likewill be apparent from the following description, drawings, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention. Additional aspects and advantagesof the present invention are set forth in the following description andclaims, particularly when considered in conjunction with theaccompanying examples and drawings.

BRIEF SUMMARY

The following aspects and embodiments thereof described and illustratedbelow are meant to be exemplary and illustrative, not limiting in scope.

In one aspect a gastric-retentive (“GR”) dosage form comprising atherapeutically effective amount of levodopa and carbidopa for oraladministration to a subject, such as a human patient, suffering from amovement disorder.

In one embodiment, the dosage form comprises a first dose of levodopaand a first dose of carbidopa. In another embodiment, the first dose oflevodopa and the first dose of carbidopa are dispersed in a polymermatrix. In another embodiment, the polymer matrix comprises at least onehydrophilic polymer. In yet another embodiment, the polymer matrixswells upon imbibition of fluid to a size sufficient for gastricretention in the stomach of a subject in a fed mode.

In one embodiment, the GR dosage form is a single layer or monolithicdosage form comprising a first dose of levodopa and a first dose ofcarbidopa as an extended release (“ER”) dosage form. In anotherembodiment, the GR dosage form has a total weight of about 400 mg toabout 900 mg, or about 500 mg to about 800 mg. In another embodiment,the GR dosage form has a total weight of about 400 mg, 550 mg, 600 mg,650 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg.

In one embodiment, the first dose of levodopa is about 100 mg to about500 mg or about 200 mg to about 300 mg. In another embodiment, the firstdose of levodopa is about 250 mg to about 350 mg or about 200 mg toabout 300 mg. In yet another embodiment, the first dose of levodopa isabout 125 mg, 150 mg, 175 mg, 200 mg 220 mg, 240 mg, 250 mg, 260 mg, 275mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or500 mg.

In one embodiment, the first dose of carbidopa is about 25 mg to about125 mg or about 50 mg to about 75 mg. In another embodiment, the firstdose of levodopa is about 60 mg to about 90 mg or about 50 mg to about75 mg. In yet another embodiment, the first dose of levodopa is about 30mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, 100 mg, 110 mg, or 130 mg.

In one embodiment, the ratio of the first dose of levodopa to the firstdose of carbidopa ranges from about 10:1 to about 1:10. In anotherembodiment, the ratio is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

In one embodiment, the dosage form further comprises an antioxidant. Inanother embodiment, the antioxidant is selected from the groupconsisting of tocopherol, sodium metabisulphite, butylatedhydroxytoluene (BHT), citric acid, cysteine HCl, butylatedhydroxyanisole, ascorbic acid and sodium ascorbate, propyl gallat,sodium sulfite, tocopherol, and sodium metabisulphite. In yet anotherembodiment, the antioxidant is present in the dosage for at a wt %(weight percent) of approximately 0.01 wt %, 0.05 wt %, 0.1 wt %, 0.5 wt%, 0.75 wt %, 1 wt %, 2 wt %, 3 wt % or 4 wt %.

In one embodiment, the at least one hydrophilic polymer comprises amixture of one or more different hydrophilic polymers. In anotherembodiment, the at least one hydrophilic polymer is selected from thegroup consisting of polyethylene oxide) (PEO), wherein the PEO has amolecular weight ranging from about 300,000 daltons to about 2,000,000Da (Daltons). In another embodiment, the PEO has a molecular weightranging from about 900,000 daltons to about 4,000,000 daltons. In yetanother embodiment, the molecular weight of the PEO has a molecularweight of approximately 600,000 Da, 900,000 Da, 1,000,000 Da, 2,000,000Da, 4,000,000 Da, 5,000,000 Da, 7,000,000 Da, 9,000,000 Da, 10,000,000Da or 12,000,000 Da.

In one embodiment, the at least one hydrophilic polymer is present inthe dosage form in an amount ranging from about 15 wt % to about 70 wt%. In another embodiment, the at least one hydrophilic polymer ispresent in the dosage form in an amount ranging from about 15 wt % toabout 65 wt %. In yet another embodiment, the at least one hydrophilicpolymer is present in the dosage form in an amount ranging from about 20wt % to about 60 wt %. In still another embodiment, the at least onehydrophilic polymer is present in the dosage form in an amount rangingfrom about 30 wt % to about 50 wt %. In still another embodiment, the atleast one hydrophilic polymer is present in the dosage form in about 20wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt %, 50 wt %, 55 wt %, or60 wt %.

In one embodiment, the GR dosage form further comprises a binder. Inanother embodiment, the binder is povidone (PVP) orhydroxypropylcellulose (HPC). In yet another embodiment, the GR dosageform comprises a binder that is present in an amount ranging from about0.1 wt % to about 20 wt % or in an amount ranging from about 2 wt % toabout 15 wt %, or in an amount ranging from about 2 wt % to about 8 wt%. In still another embodiment, the GR dosage form comprises a binderthat is present in an amount that is about 1.0 wt %, 1.1 wt %, 1.2 w %,1.4 wt %, 1.5 wt %, 1.7 wt %, 1.8 wt %, 1.9 wt %, 2.0 wt %, 2.5 wt %,3.0 wt %, 3.5 wt %, 4.0 wt %, 4.5 wt %, 5.0 wt %, 5.5 wt %, 6.0 wt %,6.5 wt %, 7.0 wt %, 7.5 wt % or 8.0 wt % of the ER portion.

In one embodiment, the GR dosage form further comprises a filler. Inanother embodiment, the filler is microcrystalline cellulose (MCC)and/or mannitol. In another embodiment, the GR dosage form comprisesabout 35 wt % to about 85 wt %, about 45 wt % to about 75 wt %, about 50wt % to about 65 wt % filler. In another embodiment, the GR dosage formcomprises a filler that is present in an amount that is about 45 wt %,50 wt %, 51 wt %, 52 wt %, 53 wt %, 55 wt %, 60 wt %, 65 wt %, 68 wt %,68 wt %, 70 wt %, 71 wt %, 72 wt %, 75 wt %, 80 wt %, or 85 wt % of thedosage form.

In one embodiment, the ER portion of the dosage form further comprises alubricant. In another embodiment, the lubricant is magnesium stearate.In another embodiment, the ER portion of the dosage form comprises alubricant that is present in an amount ranging from about 0.5% to about5.0%. In yet another embodiment, the ER portion of the dosage formcomprises a lubricant that is present in an amount that is about 0.1 wt%, 0.5 wt %, 0.75 wt %, 1.0 wt %, 1.5 wt %, 1.75 wt %, 1.80 wt %, 1.85wt %, 1.90 wt % or 2.0 wt % of the ER portion.

In one embodiment, the ER portion of the dosage form comprises a coloragent. In another embodiment, the color agent is present in an amountthat is about 2.0-5.0 wt % of the ER portion of the dosage form. In yetanother embodiment, the color agent is present in an amount that isabout 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 wt % of the ERportion.

In one embodiment, the dosage form imbibes fluid and swells to a sizebetween about 110% to about 170% of the size of the dosage form prior toimbibition of fluid. In another embodiment, the dosage form swells to asize between about 115% to about 150% of the size of the dosage formprior to imbibition of fluid. In yet another embodiment, the dosage formimbibes fluid and swells to a size between about 110% to about 170%,between about 115% to about 165%, between about 120% to about 150%,between about 125% to about 140% of the size of the dosage form prior toimbibition of fluid within 30 minutes of administration or within about30 minutes of the start of imbibition of fluid into the dosage form.

In one embodiment, the dosage form begins to erode upon swelling of thedosage form. In another embodiment, the dosage form erodes such that thesize of the dosage form begins to decrease after the first 30 minutesafter administration or after the first 30 minutes after the start ofimbibition of fluid into the dosage form.

In another embodiment, upon administering of the dosage form to asubject, the dosage form provides at least about 3 to about 8 hours ofdrug delivery to the upper gastrointestinal tract, which includes thestomach and the small intestine. In another embodiment, the dosage formprovides at least 4 hours, at least 6 hours or at least 8 hours of drugdelivery to the upper gastrointestinal tract. In yet a furtherembodiment, the dosage form provides at least about 6 hours to about 8hours of drug delivery to the upper gastrointestinal tract. In yet afurther embodiment, the dosage form provides at least about 3, 4, 5, 6,7, or 8 hours of drug delivery to the upper gastrointestinal tract.

In one embodiment, the dosage form releases substantially all of thefirst dose of levodopa and substantially all of the first dose ofcarbidopa over a period of between about 6 and 12 hours, between about 8and 10 hours, or between about 7 and 9 hours. In another embodiment, thedosage form releases substantially all of the first dose of levodopa andsubstantially all of the first dose of carbidopa over a period of about6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or 13hours. In yet another embodiment, the dosage form releases at leastabout 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% of the first dose oflevodopa and the first dose of carbidopa during a time period of about 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or 13hours after oral administration of the dosage form.

In one embodiment, in an in vitro dissolution test, the dosage formreleases about 15% to about 50% of the first dose of levodopa and about15% to about 50% of the first dose of carbidopa within about 1 hour ofthe start of the dissolution test. In another embodiment, in an in vitrodissolution test, the dosage form releases about 20% to about 40% of thefirst dose levodopa and about 20% to about 40% of the first dose ofcarbidopa within about 1 hour of the start of the dissolution test. Inone embodiment, between about 10% to about 40% of the levodopa isreleased within about 1 hour in an in vitro dissolution test.

In some embodiments, the dosage form provides an in vitro dissolutionprofile wherein for each of the first dose of levodopa and the firstdose of the carbidopa, between about 40% to about 50% of the first doseremains in the dosage form between about 1 and 2 hours afteradministration. In one embodiment, not more than 30% of the first doseof levodopa and first dose of carbidopa is released within about thefirst hour. In a further embodiment, not more than 40% of the first doseof levodopa and first dose of carbidopa is released within about thefirst hour. In another embodiment, not more than 85% of the first doseof levodopa and first dose of carbidopa is released within about 4hours. In another embodiment, not less than 50% is released after about4 hours. In yet another embodiment, not less than 60% is released afterabout 6 hours.

In one embodiment the in vitro dissolution test is a USP Type Idissolution test performed at 37° C. in an aqueous medium containing0.1N HCl. In another embodiment, the USP Type I dissolution test is runat a speed of 150 rpm.

In one embodiment the in vitro dissolution test is a USP Type 11dissolution test performed at 37° C. in an aqueous medium containing0.1N HCl. In another embodiment, the USP Type II dissolution test is runat a speed of 150 rpm.

In one another embodiment the in vitro dissolution test is a USP TypeIII dissolution test performed at 37° C. in an aqueous medium containing0.1N HCl. In another embodiment, the USP Type III dissolution test isrun at a speed of 10 dpm.

In one embodiment, the dosage form, when orally administered to asubject in a fed mode, produces a plasma profile in the subject whereinthe plasma level of levodopa is maintained for at least about 6 to about10 hours, about 8 to about 12 hours, about 6 to about 8 hours, or about7 to about 9 hours.

In one embodiment, the dosage form, when orally administered to asubject in a fed mode, results in an AUC for a 12-hour dosing intervalis between about 300 ng·hour/ml to about 1500 ng·hour/ml. In anotherembodiment, the AUC for a 12-hour dosing interval is between about 400ng·hour/ml to about 800 ng·hour/ml. In yet another embodiment, the AUCfor a 12-hour dosing interval is between about 500 ng·hour/ml to about700 ng·hour/ml.

In one embodiment, the dosage form when administered to the subjectproduces a plasma profile in the subject comprising a prolonged plasmalevel of levodopa for at least 6-10 hours or 8-12 hours maintainingtherapeutic efficacy; and a C_(max) for levodopa of between about 300ng/ml to about 1500 ng/ml and a C_(min) for levodopa of between about300 ng/ml to about 3000 ng/ml. In another embodiment, the ratio of theC_(max) to the C_(min) is less than or equal to about 4.

In one embodiment, the dosage form when administered to the subjectproduces a plasma profile in a human patient comprising a fast onsetplasma level achieved within less than about two hours followed by aprolonged plasma level of levodopa for at least 6-10 hours or 8-12 hoursmaintaining therapeutic efficacy; and a C_(max) for levodopa of betweenabout 300 ng/ml to about 1500 ng/ml of levodopa for at least 6-10 hoursor 8-12 hours maintaining therapeutic efficacy. In another embodiment,the ratio of the C_(max) to the C_(min) is less than or equal to about5.

In one embodiment, the ratio of the C_(max) to the C_(min) during a12-hour dosing interval is between about 3 to 5. In another embodiment,the ratio is greater than 1 but less than about 20, or is greater than 1but less than or equal to about 4. In yet another embodiment, the ratiois between about 1 to about 4.

In another aspect, the dosage form further comprises a second dose oflevodopa and a second dose of carbidopa which are present in animmediate release (“IR”) portion.

In one embodiment, the GR dosage form comprises an ER portion comprisinga first dose of levodopa and a first dose of carbidopa, and an IRportion comprising a second dose of levodopa and a second dose ofcarbidopa. In another embodiment, the GR dosage form is a bilayertablet, wherein the first layer is the ER portion and the second layeris the IR portion. In yet another embodiment, the GR dosage form is acapsule which comprises an ER portion and an IR portion.

In one embodiment, the ratio of the second dose of levodopa to thesecond dose of carbidopa ranges from about 10:1 to about 1:10. Inanother embodiment, the ratio is about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1,4:1, 3:1 or 2:1.

In one embodiment, the ratio of the first dose of levodopa to the firstdose of carbidopa in the ER portion is lower than the ratio of thesecond dosage of levodopa to the second dose of carbidopa in the IRportion. In another embodiment the ratio of the first dose of levodopato the first dose of carbidopa in the ER portion is about 3:1 and theratio of the second dosage of levodopa to the second dose of carbidopain the IR portion is 4:1. In yet another embodiment the ratio of thefirst dose of levodopa to the first dose of carbidopa in the ER portionis about 3:1 and the ratio of the second dosage of levodopa to thesecond dose of carbidopa in the IR portion is about 5:1.

In one embodiment, the ratio of the first dose of levodopa to the firstdose of carbidopa in the ER portion is greater than the ratio of thesecond dosage of levodopa to the second dose of carbidopa in the IRportion. In another embodiment, the ratio of the first dose of levodopato the first dose of carbidopa in the ER portion is about 4:1 and theratio of the second dosage of levodopa to the second dose of carbidopain the IR portion is about 3:1. In yet another embodiment the ratio ofthe first dose of levodopa to the first dose of carbidopa in the ERportion is 4:1 and the ratio of the second dosage of levodopa to thesecond dose of carbidopa in the IR portion is 2:1.

In one embodiment, the second dose of levodopa is about 50 mg to about150 mg or about 20 mg to about 100 mg. In another embodiment, the seconddose of levodopa is about 75 mg to about 125 mg or about 40 mg to about70 mg. In yet another embodiment, the second dose of levodopa is about40 mg, 45 mg, 50 mg, 55 mg 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or 125 mg.

In one embodiment, the second dose of carbidopa is about 15 mg to about50 mg or about 5 mg to about 25 mg. In another embodiment, the seconddose of levodopa is about 25 mg to about 40 mg or about 15 mg to about25 mg. In yet another embodiment, the second dose of levodopa is about30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, 100 mg, 110 mg, or 130 mg.

In one embodiment, the ER portion comprises about 300 mg levodopa andabout 75 mg carbidopa and the IR portion comprises about 100 mg levodopaand about 35 mg carbidopa. In another embodiment, the ER portioncomprises about 240 mg levodopa and about 60 mg carbidopa and the IRportion comprises about 60 mg levodopa and the IR portion comprisesabout 20 mg carbidopa.

In one embodiment, substantially all of the second dose of levodopa andthe second dose of carbidopa are released from the IR portion in about 1to about 5 minutes, or in about 2 to about 4 minutes after oraladministration. In another embodiment, substantially all of the seconddose of levodopa and the second dose of carbidopa are released from theIR portion within about 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6minutes, 7 minutes, or 8 minutes after oral administration.

In yet another embodiment, the IR portion of the dosage form furthercomprises a binder. In some embodiments, the binder is chosen from amongpovidone and hydroxypropylcellulose. In another embodiment, the binderis present in the IR portion of the dosage form in an amount that isabout 4.5 wt %, 5.0 wt %, 5.5 wt %, 6.0 wt %, 6.5 wt %, 7.0 wt %, 7.5 wt%, 8.0 wt %, 8.5 wt %, 9.0 wt %, 9.5 wt % or 10.0 wt % of the IRportion.

In one embodiment, the IR portion of the dosage form further comprises afiller. In another embodiment, the filler is microcrystalline cellulose(MCC) and/or mannitol. In another embodiment, the IR portion of thedosage form comprises about 35 wt % to about 85 wt %, about 45 wt % toabout 75 wt %, about 50 wt % to about 65 wt % filler. In anotherembodiment, the IR portion of the dosage form comprises a filler that ispresent in an amount that is about 45 wt %, 50 wt %, 51 wt %, 52 wt %,53 wt %, 55 wt %, 60 wt %, 65 wt %, 68 wt %, 68 wt %, 70 wt %, 71 wt %,72 wt %, 75 wt %, 80 wt %, or 85 wt % of the dosage form.

In one embodiment, the IR portion of the dosage form comprises a coloragent. In another embodiment, the color agent is present in an amountthat is about 2.0-5.0 wt % of the IR portion of the dosage form. In yetanother embodiment, the color agent is present in an amount that isabout 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 wt % of the IRportion.

In some embodiments, the bilayer tablet has a friability of no greaterthan about 0.1%, 0.2% 0.3%, 0.4%, 0.5%, 0.7% or 1.0%.

In some embodiments, the bilayer tablet has a hardness of at least about10 kilopond (also known as kilopons) (kp). In some embodiments, thetablet has a hardness of about 9 kp to about 25 kp, or about 12 kp toabout 20 kp. In further embodiments, the tablet has a hardness of about11, 12, 13, 14, 15, or 16 kp.

In some embodiments, the tablets have a content uniformity of from about85 to about 115 percent by weight or from about 90 to about 110 percentby weight, or from about 95 to about 105 percent by weight. In otherembodiments, the content uniformity has a relative standard deviation(RSD) equal to or less than about 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0% or0.5%.

In one embodiment, the IR portion further comprises an antioxidantchosen from tocopherol, sodium metabisulphite, butylated hydroxytoluene(BHT), citric acid, cysteine HCl, butylated hydroxyanisole, ascorbicacid and sodium ascorbate, and sodium metabisulphite. In yet anotherembodiment, the antioxidant is present in the dosage for at a wt %(weight percent) of approximately 0.01 wt %, 0.05 wt %, 0.1 wt %, 0.5 wt%, 0.75 wt %, 1 wt %, 2 wt %, 3 wt % or 4 wt %.

In another aspect, a pharmaceutical or gastric retentive oral dosageform comprising levodopa and carbidopa, wherein the formulation isadministered to a mammal two times in a 24 hour period (b.i.d. ortwice-daily) or three times in a 24 hour period (t.i.d. or three timesdaily) is provided.

In one embodiment, the dosage form comprising an ER portion and an IRportion produces a plasma profile in the subject comprising a fast onsetplasma level, wherein a therapeutically effective amount of levodopa ispresent in the blood plasma within less than about 0.5 hours, 1 hour,1.5 hours or 2 hours after oral administration of the dosage form,followed by a prolonged plasma level of levodopa for a period of atleast about 6 to about 10 hours or about 8 to about 12 hours. In oneembodiment, the prolonged plasma level of levodopa is maintained at alevel which is no less than 95%, 90%, 85%, 80%, 75% or 70% of theC_(max) achieved within about 12 hours of administration of the oraldosage form. In another embodiment, the prolonged plasma level oflevodopa is maintained for a period of about 6 hours, 7 hours, 8 hours,9 hours, 10 hours, 11 hours, 12 hours or 13 hours after oraladministration of the dosage form.

Also provided is a method of treating a subject suffering from amovement disorder, comprising administering a therapeutic effectiveamount of any of the describe dosage forms or pharmaceuticalformulations herein.

In one embodiment, the subject is suffering from a movement disorderincluding but not limited to Parkinson's Disease, Restless Leg Syndrome(RLS), Huntington's chorea, progressive supranuclear palsy, Wilson'sdisease, Tourette's syndrome, epilepsy, tardive dyskinesia, residualamblyopia, Angelman Syndrome, and various chronic tremors, tics anddystonias.

In one embodiment is a method for treating Parkinson's Disease (PD) byadministering a dosage form providing both immediate release andsustained release of levodopa and carbidopa.

In one embodiment, a gastric retained dosage form comprising levodopa,carbidopa, and a swellable polymer is administered to a subjectsuffering from or diagnosed with a movement disorder. In anotherembodiment, the gastric retained dosage form comprises an ER portion asdescribed above. In yet another embodiment, the gastric retained dosageform further comprises an IR portion as described above.

In one embodiment, the gastric retained dosage form comprises about 300mg levodopa and about 80 mg carbidopa. In another embodiment, thegastric retained dosage form comprises about 400 mg levodopa and about110 mg carbidopa.

In one embodiment, a gastric retained dosage form is administered to asubject in a fed mode. In another embodiment, the dosage form isadministered with a meal to the subject twice in a 24 hour period. Insome embodiments, the dosage form is administered with a meal to thesubject three times in a 24 hour period.

Also provided, is a method of making a pharmaceutical or gastricretentive dosage form comprising a first dose of levodopa, a first doseof carbidopa dispersed in an ER polymer matrix comprised of a polymerthat swells upon imbibition of fluid to a size sufficient for gastricretention in the upper gastrointestinal tract in a fed mode.

In some embodiments, the method comprises wet granulating a firstmixture that comprises levodopa, carbidopa and a binder to produce afirst granulation mixture. In another embodiment, the wet granulatingcomprises spraying a solution of binder dissolved in water onto levodopaparticles. In a further embodiment, the particles of the firstgranulation mixture are blended with a polymer and one or moreexcipients to form an ER portion of a dosage form.

In some embodiments, the one or more excipients blended with the firstgranulation mixture are chosen from among a filler, a lubricant and acolor agent.

In further embodiments, the wet granulating is a fluid bed granulationmethod. In other embodiments, the wet granulating is a high sheargranulation method.

In a further embodiment, the method comprises compressing the ER portionof the dosage form into a tablet.

In some embodiments, the wet granulation of the ER portion of the dosageform produces particles with a bulk density ranging from about 0.30 to0.40 grams/milliliter (g/ml). In other aspects, the wet granulationproduces particles with a tap density ranging from about 0.35 g/ml toabout 0.45 g/ml. In other embodiments, the wet granulation producesparticles, wherein at least about 50% of the particles have a sizegreater than 250μ. In still other embodiments, the wet granulationproduces particles wherein about 20% to about 30% of the particles havea size greater than about 150μ and less than about 250μ.

In one embodiment, the method of making a pharmaceutical and/or gastricretentive oral dosage form comprising levodopa and carbidopa furthercomprises wet granulating a second mixture comprising the levodopa, thecarbidopa, and the binder to form a second granulation mixture. In afurther embodiment, the second granulation mixture is blended with oneor more excipients to produce an IR portion of the dosage form. In yet afurther embodiment, the IR portion is compressed with the ER portion ofthe dosage form to produce a bilayer tablet.

In further embodiments, wet granulating the second mixture is achievedby fluid bed granulation. In other embodiments, wet granulating thesecond mixture is achieved by a high shear granulation method.

Additional embodiments of the present method, compositions, and the likewill be apparent from the following description, drawings, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment or aspect. Additional aspects and embodiments are set forthin the following description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

In any one of the above methods, one embodiment is a gastric retentivedosage form comprised of a dose of gabapentin and a hydrophilicswellable polymer, wherein the dosage form after administration swellsto a size that is retained in the stomach in fed mode.

In addition to the exemplary aspects and embodiments described above,further embodiments of the present method, compositions, and the likewill be apparent from the following description, drawings, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the in vitro release profile for levodopa release from theLC4SL dosage form as determined using a USP Dissolution Apparatus III at37.0±0.5° C.

FIG. 2 shows the in vitro release profile for carbidopa release from theLC4SL dosage form as determined using a USP Dissolution Apparatus III at37.0±0.5° C.

FIG. 3 shows the in vitro release profile for levodopa release from theLC4SL, LC6SL, LC6BL, Mylan and Sinemet CR dosage forms as determinedusing a USP Dissolution Apparatus III at 37.0±0.5° C.

FIG. 4 shows the cumulative release profiles for levodopa release fromthe LC4SL, LC6SL, LC6BL, and SINEMET® CR dosage forms.

FIG. 5 shows the mean levodopa plasma concentration time profiles forthe LC4SL, LC6SL, LC6BL, and SINEMET® CR dosage forms administered tofive dogs.

FIG. 6A-E show the individual levodopa plasma concentration timeprofiles for the LC4SL, LC6SL, LC6BL, and SINEMET® CR dosage formsadministered to each of the five dogs.

FIG. 7A-B show the plasma concentration time profiles for levodopa (FIG.7A) and carbidopa (FIG. 7B) for the LC4SL, LC6BL and Mylan dosage formsas determined for human subjects.

FIG. 6A-E show the individual levodopa plasma concentration timeprofiles for the LC4SL, LC6SL, LC6BL, and SINEMET® CR dosage formsadministered to each of the five dogs.

FIG. 8A-E show in vitro release profiles plotted with in vivo absorptionprofiles as a function of time.

DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey the scope of the invention to thoseskilled in the art.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

DEFINITIONS

In describing and claiming the present subject matter, the followingterminology will be used in accordance with the definitions describedbelow.

As used in this specification and the appended claims, the singularforms “a,” “an” and “the” include plural referents unless the contextclearly dictates otherwise; thus, for example, reference to “an activeagent” or “a pharmacologically active agent” includes a single activeagent as well a two or more different active agents in combination,reference to “a polymer” includes mixtures of two or more polymers aswell as a single polymer, and the like.

As used herein, the phrases “for example,” “for instance,” “such as,”and “including” are meant to introduce examples to illustrate moregeneral subject matter. These examples are provided only as an aid forunderstanding the disclosure, and are not meant to be limiting in anyfashion.

The term “about,” particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

Compounds useful in the dosage forms described herein include thosenoted herein in any of their pharmaceutically acceptable forms,including isomers such as diastereomers and enantiomers, salts,solvates, and polymorphs, as well as racemic mixtures and pure isomersof the compounds described herein, where applicable.

The term “controlled release” is intended to refer to any dosage form inwhich release of the drug is not immediate, i.e., with a “controlledrelease” formulation, oral administration does not result in immediaterelease of the drug into an absorption pool. The term is usedinterchangeably with “nonimmediate release” as defined in Remington: TheScience and Practice of Pharmacy, 20^(th) edition (Lippincott Williams &Wilkins, 2000). Examples of controlled release dosage forms include“delayed release,” “sustained release,” “extended release,” and“modified release” dosage forms. In general, however, the term“controlled release” as used herein includes any nonimmediate releaseformulation.

The terms “effective amount” or a “therapeutically effective amount”refer to the amount of drug or pharmacologically active agent to providethe desired effect without toxic effects. The amount of an agent that is“effective” may vary from individual to individual, depending on theage, weight, general condition, and other factors of the individual, ordepending on the type and severity of the disorder or disease beingtreated. An appropriate “effective” amount in any individual may bedetermined by one of ordinary skill in the art using routineexperimentation. An “effective amount” of an agent can refer to anamount that is either therapeutically effective or prophylacticallyeffective or both.

By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier,” or a “pharmaceutically acceptableacid addition salt,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects or interacting in a deleterious mannerwith any of the other components of the composition in which it iscontained. The term “pharmacologically active” (or simply “active”) asin a “pharmacologically active” derivative, refers to a derivativehaving the same type of pharmacological activity as the parent compoundand/or drug and approximately equivalent in degree. When the term“pharmaceutically acceptable” is used to refer to a derivative (e.g., asalt) of an active agent, it is to be understood that the compound ispharmacologically active as well. When the term, “pharmaceuticallyacceptable” is used to refer to an excipient, it implies that theexcipient has met the required standards of toxicological andmanufacturing testing or that it is on the Inactive Ingredient Guideprepared by the FDA, or comparable agency.

The terms “drug,” “active agent,” “therapeutic agent,” and/or“pharmacologically active agent” are used interchangeably herein torefer to any chemical compound, complex or composition that is suitablefor oral administration and that has a beneficial biological effect,preferably a therapeutic effect in the treatment or prevention of adisease or abnormal physiological condition. The terms also encompasspharmaceutically acceptable, pharmacologically active derivatives ofthose active agents specifically mentioned herein, including, but notlimited to, salts, esters, amides, prodrugs, active metabolites,analogs, and the like. When the terms “active agent,” “pharmacologicallyactive agent,” and “drug” are used, then, or when a particular activeagent is specifically identified, it is to be understood that applicantsintend to include the active agent per se as well as pharmaceuticallyacceptable, pharmacologically active salts, esters, amides, prodrugs,metabolites, analogs, etc.

The term “dosage form” refers to the physical formulation of the drugfor administration to the patient. Dosage forms include withoutlimitation, tablets, capsules, caplets, liquids, syrups, lotions,lozenges, aerosols, patches, enemas, oils, ointments, pastes, powdersfor reconstitution, sachets, solutions, sponges, and wipes. Within thecontext of the present invention, a dosage form comprising alevodopa/carbidopa formulation will generally be administered topatients in the form of tablets or capsules, although a liquidformulation is also contemplated under the invention.

The term “dosage unit” refers to a single unit of the dosage form thatis to be administered to the patient. The dosage unit will be typicallyformulated to include an amount of drug sufficient to achieve atherapeutic effect with a single administration of the dosage unitalthough where the size of the dosage form is at issue, more than onedosage unit may be necessary to achieve the desired therapeutic effect.For example, a single dosage unit of a drug is typically, one tablet,one capsule, or one tablespoon of liquid. More than one dosage unit maybe necessary to administer sufficient drug to achieve a therapeuticeffect where the amount of drug causes physical constraints on the sizeof the dosage form.

“Total daily dose” is the total amount of drug administered to thepatient in one 24 hour period, regardless of whether the protocol callsfor a once-daily, twice-daily, or thrice-daily administration of thedrug. Thus, the total amount of drug is summed for a given 24 hourperiod to determine how much total drug the patient is to beadministered in a given day. It is to be understood, however, that theamount of a drug to be administered to a particular patient will varydue to the extent of the patient's symptoms requiring treatment, thepatient's tolerance for levodopa and/or carbidopa or drugs in general,the size of the patient, and various other factors that one of ordinaryskill in the art must take into consideration.

The term “asymmetric dose” refers to the administration of more than oneunequal doses of a particular drug in a 24 hour period. For example, twoasymmetric doses of a particular drug are administered in a 24 hourperiod. Asymmetric doses are typically administered as a small dose inthe morning and a proportionally larger dose in the evening.

“Titration” is the process of ramping up the total daily amount of drugadministered to the patient. “Titration” allows the patient's body toget used to the higher dose, and ensures that the patient is preparedfor subsequent higher doses of the drug through a succession of dailydoses that are of increasing amount.

“Weaning,” which is also referred to as “tapering,” is the process ofreducing the daily total dose a patient is receiving from themaintenance dose to a lesser dose. “Weaning” occurs when a patient isexperiencing fewer of the symptoms requiring treatment or the treatingphysician would like to test whether the patient can reduce amaintenance dose. Weaning is effectively the opposite of titration, andoccurs by successively reducing a daily maintenance dose to a lowerlevel. Weaning can occur down to 0 mg of drug, depending on whether thepatient is in fact ready to completely stop taking the medication.

“Maintenance” is the dosage amount that the patient needs to reach andmaintain a desired level of relief from the symptoms under treatment.The maintenance dose is generally titrated to and maintained for adesignated period of time. As discussed above, maintenance doses mayalso be diminished by weaning. As is known by those of ordinary skill inthe art, maintenance doses should be set to minimize any side effects ofthe drug.

“Delayed release” dosage forms are a category of modified release dosageforms in which the release of the drug is delayed after oraladministration for a finite period of time after which release of thedrug is unhindered. Delayed release dosage forms are frequently used toprotect an acid-labile drug from the low pH of the stomach or whereappropriate to target the GI tract for local effect while minimizingsystemic exposure. Enteric coating is frequently used to manufacturedelayed release dosage forms.

The terms “sustained release,” and “extended release” are usedinterchangeably herein to refer to a dosage form that provides forgradual release of a drug over an extended period of time. With extendedrelease dosage forms, the rate of release of the drug from the dosageform is reduced in order to maintain therapeutic activity of the drugfor a longer period of time or to reduce any toxic effects associatedwith a particular dosing of the drug. Extended release dosage forms havethe advantage of providing patients with a dosing regimen that allowsfor less frequent dosing, thus enhancing compliance. Extended releasedosage forms can also reduce peak-related side effects associated withsome drugs and can maintain therapeutic concentrations throughout thedosing period thus avoiding periods of insufficient therapeutic plasmaconcentrations between doses.

The term “modified release” refers to a dosage form that includes bothdelayed and extended release drug products. The manufacture of delayed,extended, and modified release dosage forms are known to ordinary skillin the art and include the formulation of the dosage forms withexcipients or combinations of excipients necessary to produce thedesired active agent release profile for the dosage form.

The “gastric retentive” oral dosage forms described herein are a type ofextended release dosage form. Gastric retentive dosage forms arebeneficial for the delivery of drugs with reduced absorption in thelower GI tract or for local treatment of diseases of the stomach orupper GI tract. For example, in certain embodiments of gastric retentiveoral dosage forms of the present invention, the dosage form swells inthe gastric cavity and is retained in the gastric cavity of a patient inthe fed med so that the drug may be released for heightened therapeuticeffect. See, Hou et al., Crit. Rev. Ther. Drug Carrier Syst.20(6):459-497 (2003).

The term “half-life” is a pharmacokinetic term used to indicate thelength of time necessary to eliminate 50% of the remaining amount ofdrug present in the body.

The term “AUC” (i.e., “area under the curve,” “area under theconcentration curve,” or “area under the concentration-time curve”) is apharmacokinetic term used to refer a method of measurement ofbioavailability or extent of absorption of a drug based on a plot of anindividual or pool of individual's blood plasma concentrations sampledat frequent intervals; the AUG is directly proportional to the totalamount of unaltered drug in the patient's blood plasma. For example, alinear curve for a plot of the AUC versus dose (i.e., straight ascendingline) indicates that the drug is being released slowly into the bloodstream and is providing a steady amount of drug to the patient; if theAUC versus dose is a linear relationship this generally representsoptimal delivery of the drug into the patient's blood stream. Bycontrast, a non-linear AUC versus dose curve indicates rapid release ofdrug such that some of the drug is not absorbed, or the drug ismetabolized before entering the blood stream.

The term “C_(max)” (i.e., “maximum concentration”) is a pharmacokineticterm used to indicate the peak concentration of a particular drug in theblood plasma of a patient.

The term “T_(max)” (i.e., “time of maximum concentration” or “time ofC_(max)”) is a pharmacokinetic term used to indicate the time at whichthe C_(max) is observed during the time course of a drug administration.As would be expected, a dosage form that would include an immediaterelease as well as a gastric retentive component would have a T_(max)that is higher than the C_(max) for an immediate release dosage form,but lower than the T_(max) for a purely gastric retentive dosage form.

“Preventing,” in reference to a disorder or unwanted physiological eventin a patient, refers specifically to inhibiting or significant reducingthe occurrence of symptoms associated with the disorder and/or theunderlying cause of the symptoms.

“Treating,” “treat,” and “treatment” refer to reduction in severityand/or frequency of symptoms, elimination of symptoms and/or underlyingcause, prevention of the occurrence of symptoms and/or their underlyingcause, and improvement or remediation of damage.

The term “soluble” as used herein refers to a drug having an aqueoussolubility (measured in water at 20° C.) greater than 10%, preferablygreater than 20%, by weight. The terms “slightly soluble” and “sparinglysoluble” refer to a drug having an aqueous solubility (measured at 20°C.) in the range of 2% to 10% by weight, while drugs having an aqueoussolubility in the range of 0.001% to less than 2% by weight are referredto as “substantially insoluble.”

The terms “hydrophilic” and “hydrophobic” are generally defined in termsof a partition coefficient P, which is the ratio of the equilibriumconcentration of a compound in an organic phase to that in an aqueousphase. A hydrophilic compound has a P value less than 1.0, typicallyless than about 0.5, where P is the partition coefficient of thecompound between octanol and water, while hydrophobic compounds willgenerally have a P greater than about 1.0, typically greater than about5.0. The polymeric carriers herein are hydrophilic, and thus compatiblewith aqueous fluids such as those present in the human body.

The term “polymer” as used herein refers to a molecule containing aplurality of covalently attached monomer units, and includes branched,dendrimeric, and star polymers as well as linear polymers. The term alsoincludes both homopolymers and copolymers, e.g., random copolymers,block copolymers and graft copolymers, as well as uncrosslinked polymersand slightly to moderately to substantially crosslinked polymers, aswell as two or more interpenetrating cross-linked networks.

The term “vesicle” as used herein refers to a small (e.g., 0.01 to 1.0mm), usually spherical structure that may contain or be composed ofeither lipoidal or aqueous material, or both. Suitable vesicles include,but are not limited to, liposomes, nanoparticles, and microspherescomposed of amino acids. While vesicles are usually membrane-bound, theyneed not necessarily be membrane bound and within the context of thepresent invention, the term “vesicle” includes both membrane-bound andnon-membrane-bound structures.

The terms “swellable” and “bioerodible” (or simply “erodible”) are usedto refer to the polymers used in the present dosage forms, with“swellable” polymers being those that are capable of absorbing water andphysically swelling as a result, with the extent to which a polymer canswell being determined by the molecular weight or degree of crosslinking(for crosslinked polymers), and “bioerodible” or “erodible” polymersreferring to polymers that slowly dissolve and/or gradually hydrolyze inan aqueous fluid, and/or that physically disentangle or undergo chemicaldegradation of the chains themselves, as a result of movement within thestomach or GI tract.

A drug “release rate,” as used herein, refers to the quantity of drugreleased from a dosage form or pharmaceutical composition per unit time,e.g., milligrams of drug released per hour (mg/hr). Drug release ratesfor drug dosage forms are typically measured as an in vitro rate ofdissolution, i.e., a quantity of drug released from the dosage form orpharmaceutical composition per unit time measured under appropriateconditions and in a suitable fluid. The specific results of dissolutiontests claimed herein are performed on dosage forms or pharmaceuticalcompositions in a USP Type II apparatus and immersed in 900 ml ofsimulated intestinal fluid (SIF) at pH 6.8 and equilibrated in aconstant temperature water bath at 37° C. Suitable aliquots of therelease rate solutions are tested to determine the amount of drugreleased from the dosage form or pharmaceutical composition. Forexample, the drug can be assayed or injected into a chromatographicsystem to quantify the amounts of drug released during the testingintervals.

The in vivo “release rate” and in vivo “release profile” refer to thetime it takes for the orally administered dosage form, or the activeagent-containing layer of a bilayer or multilayer tablet (administeredwhen the stomach is in the fed mode) or the content of the activeingredient to be reduced to 0-10%, preferably 0-5%, of its original sizeor level, as may be observed visually using NMR shift reagents orparamagnetic species, radio-opaque species or markers, or radiolabels,or determined mathematically, such as deconvolution, upon its plasmaconcentration profiles.

The term “fed mode,” as used herein, refers to a state which istypically induced in a patient by the presence of food in the stomach,the food-giving rise to two signals, one that is said to stem fromstomach distension and the other a chemical signal based on food in thestomach. It has been determined that once the fed mode has been induced,larger particles are retained in the stomach for a longer period of timethan smaller particles; thus, the fed mode is typically induced in apatient by the presence of food in the stomach. The fed mode isinitiated by nutritive materials entering the stomach upon the ingestionof food. Initiation is accompanied by a rapid and profound change in themotor pattern of the upper GI tract, over a period of 30 seconds to oneminute. The change is observed almost simultaneously at all sites alongthe G.I. tract and occurs before the stomach contents have reached thedistal small intestine. Once the fed mode is established, the stomachgenerates 3-4 continuous and regular contractions per minute, similar tothose of the fasting mode but with about half the amplitude. The pylorusis partially open, causing a sieving effect in which liquids and smallparticles flow continuously from the stomach into the intestine whileindigestible particles greater in size than the pyloric opening areretropelled and retained in the stomach. This sieving effect thus causesthe stomach to retain particles exceeding about 1 cm in size forapproximately 4 to 6 hours.

The terms “subject,” “individual” or “patient” are used interchangeablyherein and refer to a vertebrate, preferably a mammal. Mammals include,but are not limited to, humans.

The term “friability,” as used herein, refers to the ease with which atablet will break or fracture. The test for friability is a standardtest known to one skilled in the art. Friability is measured understandardized conditions by weighing out a certain number of tablets(generally 20 tablets or less), placing them in a rotating Plexiglasdrum in which they are lifted during replicate revolutions by a radiallever, and then dropped approximately 8 inches. After replicaterevolutions (typically 100 revolutions at 25 rpm), the tablets arereweighed and the percentage of formulation abraded or chipped iscalculated. The friability of the tablets, of the present invention, ispreferably in the range of about 0% to 3%, and values about 1%, or less,are considered acceptable for most drug and food tablet contexts.Friability which approaches 0% is particularly preferred.

The term “tap density” or “tapped density,” as used herein, refers to ameasure of the density of a powder. The tapped density of apharmaceutical powder is determined using a tapped density tester, whichis set to tap the powder at a fixed impact force and frequency. Tappeddensity by the USP method is determined by a linear progression of thenumber of taps.

The term “bulk density,” as used herein, refers to a property of powdersand is defined as the mass of many particles of the material divided bythe total volume they occupy. The total volume includes particle volume,inter-particle void volume and internal pore volume.

The term “capping,” as used herein, refers to the partial or completeseparation of top or bottom crowns of the tablet main body. Formultilayer tablets, capping refers to separation of a portion of anindividual layer within the multilayer tablet. Unintended separation oflayers within a multilayer tablet prior to administration is referred toherein as “splitting.”

The term “content uniformity,” as used herein refers to the testing ofcompressed tablets to provide an assessment of how uniformly themicronized or submicron active ingredient is dispersed in the powdermixture. Content uniformity is measured by use of USP Method (GeneralChapters, Uniformity of Dosage Forms), unless otherwise indicated. Aplurality refers to five, ten or more tablet compositions.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entireties. However, where apatent, patent application, or publication containing expressdefinitions is incorporated by reference, those express definitionsshould be understood to apply to the incorporated patent, patentapplication, or publication in which they are found, and not to thepresent disclosure or its claims.

Exemplary Dosage Forms

Described herein is a pharmaceutical oral dosage form comprisinglevodopa and carbidopa dispersed in a polymer matrix that, upon oraladministration, swells dimensionally unrestrained, with the imbibitionof fluid to a size sufficient for gastric retention in a stomach of asubject in a fed mode. The controlled-release oral dosage form allowseffective treatment with oral administration once, twice or three timesdaily and may be used for the treatment of a movement disorder in asubject.

Levodopa, MSD, an aromatic amino acid, is a white, crystalline compound,slightly soluble in water, with a molecular weight of 197.2. It isdesignated chemically as (−)-L-alpha-amino-beta-(3,4-dihydroxybenzene)propanoic acid. Its empirical formula is C₃H₁₁NO₄ and its structuralformula is:

Carbidopa, MSD, an inhibitor of aromatic amino acid decarboxylase, is awhite, crystalline compound, slightly soluble in water, with a molecularweight of about 244.3. It is designated chemically as(−)-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene) propanoicacid monohydrate. Its empirical formula is C₁₀H₁₄N₂O₄*H2O and itsstructural formula is:

Tablet content is expressed in terms of anhydrous carbidopa, which has amolecular weight of 226.3.

It has been surprisingly discovered that a pharmaceutically acceptablegastric retentive dosage form can be formulated to provide release, inthe upper gastrointestinal tract, of a combination of levodopa andcarbidopa over an extended period of time such that oral administrationof the dosage form once or twice daily is effective for treatment of amovement disorder.

In one embodiment, a first dose of levodopa and carbidopa is present ina gastric retentive extended release dosage form, wherein the levodopaand carbidopa are dispersed in a polymer matrix that, upon oraladministration, swells dimensionally unrestrained with the imbibition offluid, to a size sufficient for gastric retention in a stomach of asubject in a fed mode. In addition, the polymer matrix becomes slippery,which provides resistance to peristalsis and further promotes gastricretention. In the presently described dosage form, the levodopa andcarbidopa may be released from the dosage form at least in part througherosion.

The combination of levodopa and carbidopa in the dosage form may vary,but typically range in ratios of levodopa to carbidopa of about 10:1 toabout 2:1, and preferably about 4:1 or about 3:1 in the dosage form.Furthermore, the rate of levodopa drug release may be proportional tothat of the carbidopa. The rate of release may occur over a period of 3,4, 5, 6, 7, 8, 9, 10, 11, 12 hours or more.

The resulting dosage form has the unexpected property of maintaininglevels of levodopa and carbidopa in the blood over extended periods oftime, for example, 8 hours, 10 hours, or 12 hours, which are effectivein treating CNS disorders including movement disorders.

The full dose of levodopa and carbidopa will typically be released fromthe dosage form during an extended period of time, for about 3 hours toabout 12 hours, preferably about 6 hours to about 8 hours, to the to theupper gastrointestinal (“GI”) tract, allowing a continuous flow of thedrugs to the proximal region of the small intestine where levodopa isbest absorbed.

The dosage forms disclosed herein are designed to be administered to asubject in a fed mode, as the dosage forms are designed to swell to asize which is large enough to be retained in a stomach in a fed mode.Such retention allows a prolonged release of active agent into thestomach.

In the normal digestive process, the passage of matter through thestomach is delayed by a physiological condition that is variouslyreferred to as the digestive mode, the postprandial mode, or the “fedmode.” Between fed modes, the stomach is in the interdigestive or“fasting” mode. The difference between the two modes lies in the patternof gastroduodenal motor activity.

In the fasting mode, the stomach exhibits a cyclic activity called theinterdigestive migrating motor complex (“IMMC”). This activity occurs infour phases:

Phase I, which lasts 45 to 60 minutes, is the most quiescent, with thestomach experiencing few or no contractions;

Phase II, characterized by sweeping contractions occurring in anirregular intermittent pattern and gradually increasing in magnitude;

Phase III, consisting of intense bursts of peristaltic waves in both thestomach and the small bowel, lasting for about 5 to 15 minutes; and

Phase IV is a transition period of decreasing activity which lasts untilthe next cycle begins.

The total cycle time for all four phases is approximately 90 minutes.The greatest activity occurs in Phase III, when powerful peristalticwaves sweep the swallowed saliva, gastric secretions, food particles,and particulate debris, out of the stomach and into the small intestineand colon. Phase III thus serves as an intestinal housekeeper, preparingthe upper tract for the next meal and preventing bacterial overgrowth.

The fed mode is initiated by nutritive materials entering the stomachupon the ingestion of food. Initiation is accompanied by a rapid andprofound change in the motor pattern of the upper gastrointestinaltract, over a period of 30 seconds to one minute. The change is observedalmost simultaneously at all sites along the G.I. tract and occursbefore the stomach contents have reached the distal small intestine.Once the fed mode is established, the stomach generates 3-4 continuousand regular contractions per minute, similar to those of the fastingmode but with about half the amplitude. The pylorus is partially open,causing a sieving effect in which liquids and small particles flowcontinuously from the stomach into the intestine while indigestibleparticles greater in size than the pyloric opening are retropelled andretained in the stomach. This sieving effect thus causes the stomach toretain particles exceeding about 1 cm in size for approximately 4 to 6hours.

Gastric retentive dosage forms described herein typically contain atleast one hydrophilic polymer in a water-swellable polymer matrix havingat least one drug dispersed therein. The polymer matrix, where in the atleast one drug is dispersed absorbs water, causing the matrix to swell,which in turn promotes retention of the dosage form in the uppergastrointestinal tract (GI) of a subject. In addition, the matricesbecome slippery, which provides resistance to peristalsis and furtherpromotes gastric retention.

With the dosage forms described herein, the rate at which the drugs arereleased by the extended release layer into the gastrointestinal tractis largely dependent on the rate at and the degree to which the polymermatrix swells. The polymer used in the dosage forms of the presentinvention should not release the drug at too rapid a rate so as toresult in a drug overdose or rapid passage into and through thegastrointestinal tract, nor should the polymer release drug too slowlyto achieve the desired biological effect. Thus, polymers that permit arate of drug release that achieves the requisite pharmacokinetics forboth the levodopa and the carbidopa for a desired duration, as may bedetermined using a USP Disintegration Test or Dissolution Test, aredetermined for use in the dosage forms described herein.

Polymers suitable for use in the dosage forms described herein includethose that both swell upon absorption of gastric fluid and graduallyerode over a time period of hours. Upon swelling of the polymer matrix,soluble drugs dispersed in the matrix will slowly dissolve in thepermeating fluid and diffuse out from the matrix. Drugs that are poorly,or sparingly, soluble are released primarily via erosion of the polymermatrix. Both levodopa and carbidopa are poorly soluble in aqueous media.Erosion initiates simultaneously with the swelling process, upon contactof the surface of the dosage form with gastric fluid. Erosion reflectsthe dissolution of the polymer beyond the polymer gel-solution interfacewhere the polymer has become sufficiently dilute that it can betransported away from the dosage form by diffusion or convection. Thismay also depend on the hydrodynamic and mechanical forces present in thegastrointestinal tract during the digestive process. While swelling anderosion occur at the same time, it is preferred herein that drug releaseshould be erosion-controlled, meaning that the selected polymer shouldbe such that complete drug release occurs primarily as a result oferosion rather than swelling and dissolution. However, swelling shouldtake place at a rate that is sufficiently fast to allow the tablet to beretained in the stomach. At minimum, for an erosional gastric retentivedosage form, there should be an extended period during which the dosageform maintains its size before it is diminished by erosion. Furthermore,the polymer which imbibes fluid to form a gastric retained, extendedrelease polymer matrix is any polymer that is non-toxic, that swells ina dimensionally unrestricted manner upon imbibition of water, and thatprovides for sustained release of at least one incorporated drug.

Water-swellable, erodible polymers suitable for use herein are thosethat swell in a dimensionally unrestrained manner upon contact withwater, and gradually erode over time. Examples of such polymers includecellulose polymers and their derivatives including, but not limited to,hydroxyalkyl celluloses, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxymethylcellulose, microcrystalline cellulose; polysaccharides andtheir derivatives; polyalkylene oxides, such as polyethylene glycols,particularly high molecular weight polyethylene glycols; chitosan;poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers;poly(vinyl pyrrolidone); starch and starch-based polymers;maltodextrins; poly(2-ethyl-2-oxazoline); poly(ethyleneimine);polyurethane; hydrogels; crosslinked polyacrylic acids; and combinationsor blends of any of the foregoing.

Further examples are copolymers, including block copolymers and graftpolymers. Specific examples of copolymers are PLURONIC® and TECTONIC®,which are polyethylene oxide-polypropylene oxide block copolymersavailable from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA.Further examples are hydrolyzed starch polyacrylonitrile graftcopolymers, commonly known as “Super Slurper” and available fromIllinois Corn Growers Association, Bloomington, Ill., USA.

Preferred swellable, erodible hydrophilic polymers suitable for formingthe gastric retentive portion of the dosage forms described herein arepoly(ethylene oxide), hydroxypropyl methyl cellulose, and combinationsof poly(ethylene oxide) and hydroxypropyl methyl cellulose. Polyethyleneoxide) is used herein to refer to a linear polymer of unsubstitutedethylene oxide. The molecular weight of the poly(ethylene oxide)polymers can range from about 9×10⁵ Daltons to about 8×10⁶ Daltons. Apreferred molecular weight poly(ethylene oxide) polymer is about 5×10⁵Daltons and is commercially available from The Dow Chemical Company(Midland, Mich.) referred to as SENTRY® POLYOX® water-soluble resins, NF(National Formulary) grade WSR Coagulant. The viscosity of a 1% watersolution of the polymer at 25° C. preferably ranges from 4500 to 7500centipoise. In terms of their viscosities, one class of preferredalkyl-substituted celluloses includes those whose viscosity is withinthe range of about 100 to about 110,000 centipoise as a 2% aqueoussolution at 20° C. Another class includes those whose viscosity iswithin the range of about 1,000 to about 4,000 centipoise as a 1%aqueous solution at 20° C.

The amount of polymer relative to the drug can vary, depending on thedrug release rate desired and on the polymer, its molecular weight, andexcipients that may be present in the formulation. The amount of polymerin the extended release portion will be sufficient however to retain atleast about 50% of the drugs within the matrix one hour after ingestion(or immersion in the gastric fluid). Preferably, the amount of polymeris such that at least 55%, 60%, 65%, 70%, 75%, or 80% of the drugsremains in the extended release matrix one hour after ingestion. Theamount of polymer is such that at least about 20%, 25%, 30%, 35%, 40%,45%, 50%, 55% or 60% of the drugs remains in the extended release matrixfour hours after ingestion. The amount of polymer is such that at leastabout 60%, 65%, 70%, 75%, 80%, or 85% of the drugs is released withinsix hours after ingestion. In all cases, however, the drugs will besubstantially all released from the matrix within about eight, nine, orten hours, and preferably within about eight hours after ingestion, andthe polymeric matrix will remain substantially intact until all of thedrug is released. The term “substantially intact” is used herein todenote a polymeric matrix in which the polymer portion substantiallyretains its size and shape without deterioration due to becomingsolubilized in the gastric fluid or due to breakage into fragments orsmall particles.

The water-swellable polymers can be used individually or in combination.Certain combinations will often provide a more controlled release of thedrug than their components when used individually.

As discussed above, the gastric retentive nature and release profiles ofa dosage form will depend partially upon the molecular weight of theswellable polymer. The polymers are preferably of a moderate to highmolecular weight (300,000 Da to 12,000,000 Da) to enhance swelling andprovide control of the release of the levodopa and carbidopa via erosionof the polymer matrix. An example of suitable poly(ethylene oxide)polymers are those having molecular weights (viscosity average) on theorder of 900,000 Da to 2,000,000 Da. Using a lower molecular weight(“MW”) polyethylene oxide, such as POLYOX™ 1105 (900,000 MW) release forboth drugs are higher. Using a higher molecular weight polyethyleneoxide (such as POLYOX™ N-60K (2,000,000 MW) or POLYOX™ WSR-301(4,000,000 MW) reduces the rate of release for both drugs. In oneembodiment of the invention, a hydroxypropylmethylcellulose polymer ofsuch molecular weight is utilized so that the viscosity of a 1% aqueoussolution at about 20° C. is about 4000 cps to greater than 100,000 cps.

The gastric retentive dosage form or the extended release portion of agastric retentive dosage form may comprise a range of hydrophilicswellable polymers both in terms of type, approximate molecular weightand weight percent. For example, a gastric retentive dosage form may beformulated to comprise about 5 wt % to about 70 wt % hydrophilicpolymer. In another embodiment, the at least one hydrophilic polymer ispresent in the dosage form in an amount ranging from about 15 wt % toabout 65 wt %. In yet another embodiment, the at least one hydrophilicpolymer is present in the dosage form in an amount ranging from about 20wt % to about 60 wt %. In still another embodiment, the at least onehydrophilic polymer is present in the dosage form in an amount rangingfrom about 30 wt % to about 50 wt %. In still another embodiment, the atleast one hydrophilic polymer is present in the dosage form in about 20wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt %, 50 wt %, 55 wt %, or60 wt %.

Combinations of different poly(ethylene oxide)s are also contemplated,with polymers of different molecular weights contributing to differentdosage form characteristics. For example, a very high molecular weightpoly(ethylene oxide) such as POLYOX™ 303 (with a number averagemolecular weight of 7 million) or POLYOX™ Coag (with a number averagemolecular weight of 5 million) may be used to significantly enhancediffusion relative to disintegration release by providing high swellingas well as tablet integrity. Incorporating a lower molecular weightpoly(ethylene oxide) such as POLYOX™ WSR N-60K (number average molecularweight approximately 2 million) with POLYOX™ 303 and/or POLYOX™ Coagincreases disintegration rate relative to diffusion rate, as the lowermolecular weight polymer reduces swelling and acts as an effectivetablet disintegrant. Incorporating an even lower molecular weightpoly(ethylene oxide) such as POLYOX™ WSR N-80 (number average molecularweight approximately 200,000) further increases disintegration rate.Alternatively, incorporating a poly(ethylene oxide) such as POLYOX™ WSRN-60K (number average molecular weight approximately 2 million) with aneven lower molecular poly(ethylene oxide) such as POLYOX™ N-1105 (numberaverage molecular weight approximately 900,000 Da) may provide extendedrelease of the drugs in the swelling dosage form which erodes in a wayto provide the desired release rate.

Hydrophilic polymers as described above are added to a gastric retentivedosage form to provide swelling to an extent that will promote retentionin a stomach in a fed mode. A typical dosage form may swell toapproximately 115% of its original volume within 30 minutes afteradministration, and at a later time may swell to a volume that is 130%,140%, 150%, 160%, 170% or more of the original volume of the dosage formprior to imbibition of fluid.

Dosage forms prepared for oral administration according to the presentdisclosure will generally contain other inactive additives (excipients)such as binders, lubricants, disintegrants, fillers, stabilizers,surfactants, coloring agents, and the like.

Binders are used to impart cohesive qualities to a tablet, and thusensure that the tablet remains intact after compression. Suitable bindermaterials include, but are not limited to, starch (including corn starchand pregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose and lactose), polyethylene glycol, waxes, and natural andsynthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone(PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC),hydroxypropyl methylcellulose, methyl cellulose, microcrystallinecellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), andVeegum.

In one embodiment, the GR dosage form comprises a binder that is presentin an amount ranging from about 0.1 wt % to about 20 wt % or in anamount ranging from about 2 wt % to about 15 wt %, or in an amountranging from about 2 wt % to about 8 wt %. In another embodiment, the GRdosage form comprises a binder that is present in an amount that isabout 1.0 wt %, 1.1 wt %, 1.2 wt % 1.4 wt %, 1.5 wt %, 1.7 wt %, 1.8 wt%, 1.9 wt %, 2.0 wt %, 2.5 wt %, 3.0 wt %, 3.5 wt %, 4.0 wt %, 4.5 wt %,5.0 wt %, 5.5 wt %, 6.0 wt %, 6.5 wt %, 7.0 wt %, 7.5 wt % or 8.0 wt %of the dosage form.

Fillers include, for example, materials such as silicon dioxide,titanium dioxide, alumina, talc, kaolin, powdered cellulose, andmicrocrystalline cellulose, as well as soluble materials such asmannitol, urea, sucrose, lactose, lactose monohydrate, dextrose, sodiumchloride, and sorbitol. Solubility-enhancers, including solubilizers perse, emulsifiers, and complexing agents (e.g., cyclodextrins), may alsobe advantageously included in the present formulations. In oneembodiment, the filler is microcrystalline cellulose (MCC) or mannitolor a mixture of and mannitol. (MCC) and/or mannitol. In anotherembodiment, a GR dosage form comprises about 35 wt % to about 85 wt %,about 45 wt % to about 75 wt %, about 50 wt % to about 65 wt % filler.In another embodiment, the GR dosage form comprises a filler that ispresent in an amount that is about 45 wt %, 50 wt %, 51 wt %, 52 wt %,53 wt %, 55 wt %, 60 wt %, 65 wt %, 68 wt %, 68 wt %, 70 wt %, 71 wt %,72 wt %, 75 wt %, 80 wt %, or 85 wt % of the dosage form.

Lubricants are used to facilitate tablet manufacture, promoting powderflow and preventing particle capping (i.e., particle breakage) whenpressure is relieved. Useful lubricants are magnesium stearate (in aconcentration of from 0.25 wt % to 3 wt %, preferably 0.2 wt % to 1.0 wt%, more preferably about 0.5 wt %), calcium stearate, stearic acid, andhydrogenated vegetable oil (preferably comprised of hydrogenated andrefined triglycerides of stearic and palmitic acids at about 1 wt % to 5wt %, most preferably less than about 2 wt %). Solubility-enhancers,including solubilizers per se, emulsifiers, and complexing agents (e.g.,cyclodextrins), may also be advantageously included in the presentformulations. Stabilizers, as well known in the art, are used to inhibitor retard drug decomposition reactions that include, by way of example,oxidative reactions.

The formulations are typically in the form of tablets. Otherformulations contain the matrix/active agent particles in capsules. Theencapsulating material should be highly soluble so that the particlesare freed and rapidly dispersed in the stomach after the capsule isingested. Such dosage forms are prepared using conventional methodsknown to those in the field of pharmaceutical formulation and describedin the pertinent texts, e.g., in Gennaro, A. R., editor. “Remington: TheScience & Practice of Pharmacy”, 21st ed., Williams & Williams, and inthe “Physician's Desk Reference”, 2006, Thomson Healthcare.

The tablets described herein may have individual layers, each containinglevodopa and carbidopa, for delivering the component drug(s) in theimmediate release or the extended release mode. For example, a layer forimmediate release of levodopa and carbidopa can be added to a layercontaining both drugs for extended release.

Alternative gastric retentive drug delivery systems include theswellable bilayer described by Franz, et al., U.S. Pat. No. 5,232,704;the multi-layer tablet with a band described by Wong, et al., U.S. Pat.No. 6,120,803; the membrane sac and gas generating agent described inSinnreich, U.S. Pat. No. 4,996,058; the swellable, hydrophilic polymersystem described in Shell, et al., U.S. Pat. No. 5,972,389, and Shell,et al., WO 9855107, and the pulsatile gastric retentive dosage form byCowles et al., U.S. Pub. No. 2009/0028941, all of which are incorporatedherein by reference.

In a preferred embodiment, the gastric retentive dosage form comprisesan extended release component (ER layer or portion) and an immediaterelease component (IR layer or portion). The ER component comprises theat least one hydrophilic polymer in a water-swellable polymer matrixwhich swells upon imbibition of fluid to a size large enough to promotegastric retention. Both the extended release and immediate releasecomponents contain levodopa and carbidopa.

In one embodiment, the dosage form is a bilayer tablet comprising animmediate release layer and an extended release layer. Bilayer tabletsare known in the art, and the skilled artisan will be capable of theirpreparation using the methods disclosed herein along with commonlyavailable methods.

In one embodiment, the immediate release portion comprises levodopa andcarbidopa at lower amounts as compared to the amounts of levodopa andcarbidopa in the extended release layer of the dosage form. In anotheraspect, the amount of levodopa in the immediate release portion isgenerally between about 2 to 5, more typically between 3 to 4 times theamount of carbidopa in the immediate release portion. In one embodiment,the ratio levodopa to carbidopa in the immediate release portion isabout 3:1. In a preferred embodiment, the ratio of levodopa to carbidopain the immediate release portion is about 3:1.

In a preferred aspect, the immediate release portion is in contact withthe extended release portion.

An optional sub-coat layer may be employed when it is desirable toprotect the drug in the drug layer from a component in a protectivelayer. For example, a protective layer that serves as an enteric coatingmay comprise an acidic component, and the optional sub-coat would beincluded to protect the drug from such an acidic component. The sub-coatlayer should allow for relatively immediate release of the drug layeronce the protective layer is removed. Examples of suitable materials forthe sub-coat layer may include, for example, OPADRY® YS-1-10699, OPADRY®YS-1-19025-A-Clear and OPADRY-03K (supplied by Colorcon, Pa.). Thesub-coat layer may also contain additional excipients, including anydescribed elsewhere herein, as well as alkaline compounds such as bases,salts, and the like. The thickness of the sub-coat layer is typicallydetermined by the manufacturing process percentage weight gainspecification but can be, for example, within the range of about 10-50μm.

The immediate release portion may further comprise excipients such asbinders, lubricants, disintegrants, superdisintegrants, fillers,stabilizers, surfactants, coloring agents, and the like, as describedabove for the extended release component. In some embodiments, thebinder within the immediate release portion is hydroxypropylcellulose(e.g., Klucel E) or polyvinylpyrrolidone. The binder in the immediaterelease layer may be present in an amount ranging from about 0-20 wt %.

Disintegrants or superdisintegrants are used to facilitatedisintegration of the tablet, thereby increasing the erosion raterelative to the dissolution rate, and are generally starches, clays,celluloses, algins, gums, or crosslinked polymers (e.g., crosslinkedpolyvinyl pyrrolidone). In some embodiments, the superdisintegrant iscroscarmellose sodium (Ac-Di-Sol®) and is present in an amount rangingfrom about 0.5 wt % to about 10 wt %. The disintegrant orsuperdisintegrant may be present in the immediate release component inan amount ranging from about 0.5 wt % to about 2 wt %, or may be presentis an amount approximating 0.5 wt %, 1.0 wt %, 1.5 wt %, 2.0 wt %, 2.5wt %, 3.0 wt %, 4.0 wt %, 5.0 wt %, 6.0 wt %, 7.0 wt %, 8.0 wt %, 9.0 wt% or 10.0 wt %.

In one embodiment, the disintegrant or superdisintegrant is sprayed ontothe granulation mixture during granulation. In another embodiment, thedisintegrant or super disintegrant is added to the active granulesduring blending of the granules with the additional fillers and/orexcipients. In yet another embodiment, the disintegrant orsuperdisintegrant is added to the active granules both duringgranulation and during blending of the active granules with excipients.

The immediate release portion may release at least 80-100% of the activeagents within the first hour, first 30 minutes, or first 15 minutesafter oral administration. Administration to the subject of a dosageform comprising the immediate release portion may provide a fast onsetplasma level of levodopa sufficient to provide therapeutic efficacy tothe subject. In one embodiment, the efficacious threshold for treatmentof Parkinson's Disease is about 300 ng/mi. In another embodiment,administration to a subject of a dosage form comprising the immediaterelease portion provides a plasma level of levodopa of at least about300 nm/ml within about 30 minutes, 45 minutes, 60 minutes, 90 minutes or2 hours after administration of the dosage form.

Is it understood by the skilled artisan that delivery time or durationof drug release by a particular dosage form is distinct from theduration of drug delivery by the dosage form. As an example, while anextended release dosage form may release one or more drugs over a periodof 3, 4 or more hours, depending on the half-life of the drug and thetime of transit of that drug through the gastrointestinal tract, therelevant sites of absorption will be exposed for a period of time beyondthe time of drug release from the dosage form. Thus, for example, adosage form that releases one or more drugs over a period ofapproximately 8 hours may be providing delivery of that drug for aperiod of approximately 12 hours.

The dosage form, as presently described, possesses the additionaladvantageous feature of being formulated as a standard oral dosage size,then after administration, imbibing water from the gastric fluid andswelling to a size large enough to be retained in the stomach in a fedmode. This is particularly important for subjects who experiencedifficulty in swallowing, such as subjects suffering from Parkinson'sDisease.

Other alternatives for incorporating the immediate release pulse withthe delayed release pulse will be apparent to those of skill in the artupon consideration of this disclosure.

Dosage forms that provide more than two pulses of drug release arecontemplated, and a skilled artisan will appreciate the modifications tothe dosage forms described above to provide a third, fourth or furtherdrug dose pulse. Multiple pulses are possible using variations of theembodiments described herein. For dosage forms using erodible inserts, aplurality of pulses may be obtained by using more than two identical ordifferent erodible inserts in the dosage form, in which the differentinserts provide different erosion times. For dosage forms comprisingtablet cores and/or beads, additional pulses may be obtained by using aplurality of gastric retentive layers alternated with layers comprisingthe active agent.

For any of the embodiments, the optional initial (i.e., immediaterelease) pulse of drug can be combined with the delayed release pulse inany suitable manner. In general, the initial pulse of drug is releasedin the stomach rapidly upon administration. The second (i.e., delayed)pulse of active agent may be prepared such that it followsadministration of the dosage form at any time, and the skilled artisanwill understand in view of the disclosure herein how to provide thedesired time of release. For example, increasing the thickness of thewalls of the gastric retentive insert will increase the time delaybetween administration of the dosage form and release of the delayedpulse of drug. The optimal time delay between administration of thedosage form and release of the delayed pulse will depend on a number offactors, such as the condition being treated, the physicalcharacteristics and daily routine of the patient being treated, and thelike. Additional details of such pulsatile dosage forms are described inU.S. Patent Publication No. 2009/0028941 (herein incorporated byreference).

In various embodiments, the delayed pulse will release active agent tothe duodenum and/or the small intestine of the patient within about 2 to12 hours after administration of the dosage form, for example withinabout 3 to 9 hours, or for example within about 4 hours to 8 hours.Release of the delayed release pulse may be targeted for about 3 hours,4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11hours, or 12 hours after administration of the dosage form. As a furtherexample, release of the delayed release pulse may be target for betweenabout 2 hours to 4 hours, or between about 3 hours to 5 hours, orbetween about 5 hours to 7 hours, or between about 6 hours to 8 hoursafter administration of the dosage form.

Generally, the initial pulse (when present) releases a dose of activeagent or drug that is between about 0.25 and 20 times the dose of activeagent or drug that is present in the delayed pulse. Measured as a ratio,the drug dose ratio of the initial to delayed pulses may be about 0.25to 4, or 0.5 to 2, or 0.75 to 1.25, and can be 1 to 1. The amount ofactive agent in the formulation typically ranges from about 0.05 wt % toabout 95 wt % based on the total weight of the formulation. For example,the amount of active agent may range from about 0.05 wt % to about 50 wt%, or from about 0.1 wt % to about 25 wt %, or from about 1 wt % toabout 15 wt %. Alternatively, the amount of active agent in theformulation may be measured so as to achieve a desired dose,concentration, plasma level upon administration, or the like. The amountof active agent may be calculated to achieve a specific dose (i.e., unitweight of active agent per unit weight of patient) of active agent.Furthermore, the treatment regimen may be designed to sustain apredetermined systemic level of active agent. For example, formulationsand treatment regimen may be designed to provide an amount of activeagent that ranges from about 0.001 mg/kg/day to about 100 mg/kg/day foran adult. One of skill in the art will appreciate that dosages may varydepending on a variety of factors, including physical characteristics ofthe patient and duration of treatment regimen.

Numerous materials useful for manufacturing dosage forms describedherein are described in Remington: The Science and Practice of Pharmacy,20^(th) edition (Lippincott Williams & Wilkins, 2000) and Ansel et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, 6^(th) Ed.(Media, Pa.: Williams & Wilkins, 1995). Pharmaceutically acceptableadditives or excipients include binders (e.g., ethyl cellulose, gelatin,gums, polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol,starch, sugars, waxes), disintegrants, coloring agents, diluents (e.g.,calcium sulfate, cellulose, dicalcium phosphate, kaolin, lactose,mannitol, microcrystalline cellulose, sodium chloride, sorbitol, starch,sucrose), flavoring agents, glidants (e.g., colloidal silicon dioxide,talc), and lubricants (e.g., calcium stearate, glyceryl behenate,hydrogenated vegetable oils, magnesium stearate, polyethylene glycol,sodium stearyl fumarate, stearic acid, stearyl behenate, talc),sweeteners, polymers, waxes, and solubility-retarding materials. Thedosage forms described herein can be made by techniques that are wellestablished in the art, including wet granulation, fluid-bedgranulation, dry granulation, direct compression, and so forth.

A delayed pulse of drug released from the dosage forms is provided byincorporating the drug into a gastric-retentive matrix. If the drug tobe administered is acid sensitive, then, as for the drug delivered inthe initial pulse, the drug delivered in the delayed pulse is acidprotected by using, for example, an enteric coating and/or is formulatedwith a base.

Various embodiments of dosage forms for delivery of levodopa andcarbidopa are contemplated. In one embodiment, an immediate-releasecompartment comprising a blend of levodopa and/or carbidopa and one ormore polymers is surrounded by an extended-release compartment. Theextended release compartment is comprised of a hydrophilic polymer, andother components to provide the desirable release rate, such as a firstorder release which is interrupted after a period of extended drugrelease by a pulse of one or both drugs from the immediate-releasecompartment. In another embodiment, the dosage form comprises twoseparate immediate release compartments, with one or both drugs, andeach immediate release compartment is surrounded or encased by a scoredextended release compartment. The scored extended release compartmentallows the dosage form to be separated into two individual portions,providing the option for a patient to take a smaller dose. In anotherembodiment, one or both of levodopa and carbidopa are incorporated intoany of the dosage forms described herein in micronized form, optionallyadmixed with an inert particle or carrier. A micronized form of the drugcan be incorporated into one or both of an immediate release compartmentand an extended release compartment. A skilled artisan will appreciatethat a dosage form with a plurality of layers, such as an immediaterelease compartment encased by an extended release compartment which isencased by a second immediate release compartment, is contemplated.

The dosage forms are intended for oral dosage administration. Preferredoral dosage forms include tablets, capsules, and the like. Tablets maycomprise, for example, a flavored base such as compressed lactose,sucrose and acacia or tragacanth and an effective amount of an activeagent. Tablets can be prepared by common tabletting methods that involvemixing, comminution, and fabrication steps commonly practiced by andwell known to those skilled in the art of manufacturing drugformulations. Examples of such techniques are: (1) direct compressionusing appropriate punches and dies, typically fitted to a suitablerotary tabletting press; (2) injection or compression molding; (3)granulation by fluid bed, by low or high shear granulation, or by rollercompaction, followed by compression; (4) extrusion of a paste into amold or to an extrudate to be cut into lengths; (5) coating techniques,including pan-coating, fluid-bed coating and bottom spray methods(Wurster) and other film coating methods; and (6) powder layering.

When tablets are made by direct compression, the addition of lubricantsmay be helpful and is sometimes important to promote powder flow and toprevent breaking of the tablet when the pressure is relieved. Examplesof typical lubricants are magnesium stearate (in a concentration of from0.25% to 3% by weight, preferably about 1% or less by weight, in thepowder mix), stearic acid (0.5% to 3% by weight), and hydrogenatedvegetable oil (preferably hydrogenated and refined triglycerides ofstearic and palmitic acids at about 1% to 5% by weight, most preferablyabout 2% by weight). Additional excipients may be added as granulatingaids (low molecular weight HPMC at 2-5% by weight, for example), binders(microcrystalline cellulose, for example), and additives to enhancepowder flowability, tablet hardness, and tablet friability and to reduceadherence to the die wall. Other fillers and binders include, but arenot limited to, lactose (anhydrous or monohydrate), maltodextrins,sugars, starches, and other common pharmaceutical excipients. Theseadditional excipients may constitute from 1% to 50% by weight, and insome cases more, of the tablet.

In one aspect, a method of making a gastric retentive extended-releasedosage form as a single layer tablet comprising wet granulation levodopaand carbidopa with the binder is provided. The wet granulation can be afluid-bed or high shear granulation method. The granulated particles arethen blended with additional excipients as needed to form a mixturewhich is then compressed to form tablets.

Extended release polymer matrices comprising levodopa and carbidopa canbe made using, for example, POLYOX™ 1105 (approximate molecular weightof 900,000 Daltons), POLYOX™ N-60K (approximate molecular weight of2,000,000 Daltons), and/or POLYOX™ WSR-301 (approximate molecular weightof 4,000,000 Daltons). Additional polymers appropriate for use informulating extended release polymer matrices are discussed in moredetail above. Prior to compression, components can be granulated using atop spray fluid bed granulator

After fluid bed granulation and drying of the resultant particles,batches are characterized with respect to properties such as final Losson Drying (LOD), bulk density, tap density, and particle size.

Loss on Drying (LOD) is determined after each granulation using theMoisture Analyzer. One 1 gram (g) samples are taken and loaded into themoisture analyzer. The sample is run for 5 minutes at a temperature of105° C.

Bulk and tap densities can be determined as follows. A graduatedcylinder is filled with a certain amount of material (82-88 g), and thevolume recorded to determine the material bulk density. Tap density canbe determined with a help of a Tap Density Tester by exposing thematerial to 100 taps per test and recording the new volume.

Particle size determination is performed immediately after granulation,after sieving through 20 mesh screen to remove agglomerates. Particlediameter is determined with a sieve-type particle diameter distributiongauge using sieves with openings of 44, 53, 75, 106, 150, and 250 mesh.Fractions are weighed on Mettler balance to estimate size distribution.This provides determination of the quantitative ratio by particlediameter of composition comprising extended release particles. Sieveanalysis according to standard United States Pharmacopoeia methods(e.g., USP-23 NF 18), may be done such as by using a Meinzer II SieveShaker.

The granulated mixture can be blended with the polymer, filler andlubricant in a V-blender. The resultant mixture can be compressed intomonolithic, single-layer tablets using a Manesty® BB4 press, with amodified oval tool. Tablets may be prepared at a rate, for example, ofapproximately 800 tablets per minute.

Tablets are then characterized with respect to disintegration anddissolution release profiles as well as tablet hardness, friability andcontent uniformity.

Dissolution profiles for the tablets are determined in a USP apparatus.For example, a USP Apparatus 1 (basket), run at 100 or 150 revolutionsper minute (rpm), a USP Apparatus 2 (paddle), run at 100 or 150 rpm, ora USP Apparatus 3 (reciprocating cylinder) run at 10, 20, or 20 cyclesper minute (cpm) or dips per minute (dpm). In all cases, the dissolutionmedium contains 0.1 N Hydrochloric acid (HCl), maintained at atemperature of 37±0.5° C. Cumulative drug release over time isrepresented as a percent of labeled claim (% LC) for drug content and isplotted as a function of dissolution medium sampling time. The resultingcumulative dissolution profiles for the tablets are based upon atheoretical percent active added to the formulations.

Tablet hardness changes rapidly after compression as the tablet cools. Atablet that is too hard may not break up and dissolve into solutionbefore it passes through the body. In the case of the presentlydisclosed gastric retentive dosage forms, a tablet that is too hard maynot be able to imbibe fluid rapidly enough to prevent passage throughthe pylorus in a stomach in a fed mode. A tablet that is too soft maybreak apart, not handle well, and can create other defects inmanufacturing. A soft tablet may not package well or may not staytogether in transit.

After tablets are formed by compression, it is desired that the tabletshave a strength of at least 9 Kiloponds to 25 Kiloponds (Kp)/cm²,preferably at least about 12 Kp to 20 (Kp)/cm². A hardness tester isused to determine the load required to diametrically break the tablets(crushing strength) into two equal halves. The fracture force may bemeasured using a Venkel Tablet Hardness Tester, using standard USPprotocols.

Friability is a well-known measure of a tablet's resistance to surfaceabrasion that measures weight loss in percentage after subjecting thetablets to a standardized agitation procedure. Friability properties areespecially important during any transport of the dosage form as anyfracturing of the final dosage form will result in a subject receivingless than the prescribed medication. Friability can be determined usinga Roche Friability Drum according to standard USP guidelines whichspecifies the number of samples, the total number of drum revolutionsand the drum rpm to be used. Friability values of from 0.8% to 1.0% areregarded as constituting the upper limit of acceptability.

The prepared tablets are tested for content uniformity to determine ifthey meet the pharmaceutical requirement of <6% relative standarddeviation (RSD). Each tablet is placed in a solution of 1.0 N HCl andstirred at room temperature until all fragments have visibly dissolved.The solution containing the dissolved tablet is analyzed by HPLC.

In addition to the foregoing components, it may be necessary ordesirable in some cases (depending, for instance, on the particularcomposition or method of administration) to incorporate any of a varietyof additives, e.g., components that improve drug delivery, shelf-lifeand patient acceptance. Suitable additives include acids, antioxidants,antimicrobials, buffers, colorants, crystal growth inhibitors, defoamingagents, diluents, emollients, fillers, flavorings, gelling agents,fragrances, lubricants, propellants, osmotic modifiers, thickeners,salts, solvents, surfactants, other chemical stabilizers, or mixturesthereof. Examples of these additives can be found, for example, in M.Ash and I. Ash, Handbook of Pharmaceutical Additives (Hampshire,England: Gower Publishing, 1995), the contents of which are hereinincorporated by reference.

Guidance is provided herein for the administration of the dosage formsof the disclosure. It will be appreciated by the skilled artisan,however, that modifications to dosage, regimen, etc. may be required andis best determined by the practitioner on a patient-by-patient basis.The skilled practitioner will be capable of making such modificationsbased on commonly available knowledge. The dosage forms are typicallyemployed for once-a-day oral administration.

The formulations described herein may be presented in unit dose form orin multi-dose containers with an optional preservative to increase shelflife. Also contemplated are kits for the treatment of any of theconditions described herein, or any of the conditions that may betreated using the dosage forms described herein. The kit comprises thedosage form in either a single unit container or a multiple unitcontainer, and may further comprise instructions for dosage oradministration, package inserts, and the like.

In another aspect, a method for treating a subject suffering from amovement disorder by oral administration of a gastric retentive extendedrelease dosage form as described above is provided.

The method presently disclosed is useful for treating numerous movementdisorders include, by way of illustration and not limitation,Parkinson's Disease, Restless Leg Syndrome (RLS), Huntington's chorea,progressive supranuclear palsy, Wilson's disease, Tourette's syndrome,epilepsy, tardive dyskinesia, and various chronic tremors, tics anddystonias.

Generally, the frequency of administration of a particular dosage formis determined to provide the most effective results in an efficientmanner without overdosing and varies according to the followingcriteria: (1) the characteristics of the particular drug(s), includingboth its pharmacological characteristics and its physicalcharacteristics, such as solubility; (2) the characteristics of theswellable matrix, such as its permeability; and (3) the relative amountsof the drug and polymer. In most cases, the dosage form is prepared suchthat effective results are achieved with administration once every eighthours, once every twelve hours, or once every twenty-four hours. Aspreviously discussed, due to the physical constraints placed on a tabletor capsule that is to be swallowed by a patient, most dosage forms canonly support a limited amount of drug within a single dosage unit.

In one embodiment, the dosage form allows a dosing frequency of twotimes a day (b.i.d.) or three times a day (t.i.d.) to result insustained plasma concentration of levodopa or both levodopa andcarbidopa as compared to current immediate or sustained release productswhich require more frequent administration for therapeutic efficacy.

Within the context of the present disclosure, the gastric retentivedosage forms have the advantage of improving patient compliance withadministration protocols because the drugs may be administered in aonce-daily or twice-daily dosing regimen, rather than the multipledosing administrations necessary for currently available dosage forms oflevodopa and carbidopa in order to maintain a desired level of relief.One embodiment of the invention relates to a method of administering atherapeutically effective amount of levodopa and carbidopa to a patientin need thereof, comprising administering levodopa and carbidopa orpharmaceutically acceptable salts thereof, in a gastric retentive dosageform once in the morning or evening in a once a day daily regime.Another embodiment comprises administering the gastric retentive dosageform twice a day, for example once in the morning and once in theevening in a twice a day daily dosage regime.

For all modes of administration, the gastric retentive dosage formsdescribed herein are preferably administered in the fed mode, i.e., withor just after consumption of a small meal (see U.S. Publication No.2003/0104062, herein incorporated by reference). When administered inthe evening fed mode, the gastric retentive dosage form may provide thesubject with continued relief from pain through the night and into thenext day. The gastric retentive dosage form of the present invention isable to provide pain relief for an extended period of time because thedosage form allows for both extended release of the acetaminophen andopioid and the superior absorption of the drugs in the GI tract.

In some aspects, the postprandial or fed mode can also be inducedpharmacologically, by the administration of pharmacological agents thathave an effect that is the same or similar to that of a meal. Thesefed-mode inducing agents may be administered separately or they may beincluded in the dosage form as an ingredient dispersed in the shell, inboth the shell and the core, or in an outer immediate release coating.Examples of pharmacological fed-mode inducing agents are disclosed inU.S. Pat. No. 7,405,238, entitled “Pharmacological Inducement of the FedMode for Enhanced Drug Administration to the Stomach,” inventors Markey,Shell, and Berner, the contents of which are incorporated herein byreference.

It will be recognized by those of skill in the art that the methods ofadministration and dosage forms described herein are also suitable fortherapeutic agents other than those previously mention, including drugsand active agents that are suitable for treatment of conditions otherthan CNS and related conditions. Such therapeutic agents include thosecommonly administered via the oral route, those where oraladministration is desirable, and those that have not previously beenadministered via the oral route but that would benefit from delivery viathe oral route using the methods and dosage forms described herein.

In one embodiment, the dosage forms described herein find use for drugsthat have a reduced absorption in the lower GI tract and a reducedbioavailability due to first-pass metabolism. Sparingly soluble drugsparticularly can suffer from both of these absorption issues, sincehepatic metabolism tries to make these sparingly soluble drugs morepolar to eliminate them vial renal clearance, and the drug's poorsolubility makes the upper GI tract too short for adequate absorption.Any of the drugs in the examples listed below that are sparingly solubleare contemplated to benefit from administration in a dosage form asdescribed herein.

Alternative active agents for use in the dosage forms described hereinmay include anti-microbial agents, anti-diabetic agents, analgesics,anti-inflammatory agents, anti-convulsant agents, CNS and respiratorystimulants, neuroleptic agents, hypnotic agents and sedatives,anxiolytics and tranquilizers, other anti-cancer drugs includingantineoplastic agents, antihyperlipidemic agents, antihypertensiveagents, cardiovascular preparations, anti-viral agents, sex steroids,muscarinic receptor agonists and antagonists, and macromolecular activeagents such as DNA, RNA, proteins, and peptide drugs. Some examples ofthese active agents are provided below.

Analgesics useful in the dosage forms described herein include by way ofexample non-opioid analgesic agents such as apazone, etodolac,difenpiramide, indomethacin, meclofenamate, mefenamic acid, oxaprozin,phenylbutazone, piroxicam, and tolmetin; and opioid analgesics such asalfentanil, buprenorphine, butorphanol, codeine, drocode, fentanyl,hydrocodone, hydromorphone, levorphanol, meperidine, methadone,morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene,sufentanil, and tramadol. Additional analgesic agents contemplated foruse in the dosage forms described herein include non-steroidalanti-inflammatory agents (NSAIDs). Examples of suitable commerciallyavailable opioid analgesics useful in the dosage forms include PERCOCET®(oxycodone; Dupont Merck Pharmaceuticals, Wilmington, Del.), ULTRACET®(tramadol; Johnson & Johnson, New Brunswick, N.J.), and CLONOPIN™(clonazepam; Hoffmann-LaRoche, Nutley, N.J.). It will be appreciatedthat combinations of analgesic agents can be used in a single dosageform, for example, an opioid analgesic in combination with a non-opioidanalgesic. Combinations of hydrocodone or hydromorphone and ibuprofen oracetaminophen are exemplary of such combinations.

Anti-cancer agents, including antineoplastic agents useful in the dosageforms include by way of example paclitaxel, docetaxel, camptothecin andits analogues and derivatives (e.g., 9-aminocamptothecin,9-nitrocamptothecin, 10-hydroxy-camptothecin, irinotecan, topotecan,20-O-β-glucopyranosyl camptothecin), taxanes (baccatins, cephalomannineand their derivatives), carboplatin, cisplatin, interferon-α_(2A),interferon-α_(2B), interferon-α N₃ and other agents of the interferonfamily, levamisole, altretamine, cladribine, tretinoin, procarbazine,dacarbazine, gemcitabine, mitotane, asparaginase, porfimer, mesna,amifostine, mitotic inhibitors including podophyllotoxin derivativessuch as teniposide and etoposide and vinca alkaloids such asvinorelbine, vincristine and vinblastine.

Anti-convulsant (anti-seizure) agents useful in the dosage forms includeby way of example azetazolamide, carbamazepine, clonazepam, clorazepate,ethosuximide, ethotoin, felbamate, lamotrigine, mephenytoin,mephobarbital, phenytoin, phenobarbital, primidone, trimethadione,vigabatrin, topiramate, and the benzodiazepines. Benzodiazepines, as iswell known, are useful for a number of indications, including anxiety,insomnia, and nausea. Examples of suitable commercially availableanti-convulsants useful in the dosage forms of include TEGRETOL®(carbamazepine; Novartis, Summit, N.J.), DILANTIN® (Pfizer Inc., NewYork, N.Y.) and LAMICTAL® (lamotrigine (GlaxoSmithKline, Philadelphia,Pa.).

Anti-depressant agents useful in the dosage forms include by way ofexample the tricyclic antidepressants LIMBITROL® (amitriptyline;Hoffmann-LaRoche, Nutley, N.J.), TOFRANIL® (imipramine; Tyco Healthcare,Mansfiled, Mass.), ANAFRANIL™ (clomipramine; Tyco Healthcare, Mansfield,Mass.), and NORPRAMIN® (desipramine; Sanofi-Aventis, Bridgewater, N.J.).

Anti-diabetic agents useful in the dosage forms include by way ofexample acetohexamide, chlorpropamide, ciglitazone, gliclazide,glipizide, glucagon, glyburide, miglitol, pioglitazone, tolazamide,tolbutamide, triampterine, and troglitazone.

Anti-hyperlipidemic agents useful in the dosage forms include by way ofexample lipid-lowering agents, or “hyperlipidemic” agents, such asHMG-CoA reductase inhibitors such as atorvastatin, simvastatin,pravastatin, lovastatin and cerivastatin, and other lipid-loweringagents such as clofibrate, fenofibrate, gemfibrozil and tacrine.

Anti-hypertensive agents useful in the dosage forms include by way ofexample amlodipine, benazepril, darodipine, diltiazem, doxazosin,enalapril, eposartan, esmolol, felodipine, fenoldopam, fosinopril,guanabenz, guanadrel, guanethidine, guanfacine, hydralazine, losartan,metyrosine, minoxidil, nicardipine, nifedipine, nisoldipine,phenoxybenzamine, prazosin, quinapril, reserpine, terazosin, andvalsartan.

Anti-inflammatory agents useful in the dosage forms include by way ofexample nonsteroidal anti-inflammatory agents such as the propionic acidderivatives as ketoprofen, flurbiprofen, ibuprofen, naproxen,fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin,pranoprofen, suprofen, alminoprofen, butibufen, and fenbufen; apazone;diclofenac; difenpiramide; diflunisal; etodolac; indomethacin;ketorolac; meclofenamate; nabumetone; phenylbutazone; piroxicam;sulindac; and tolmetin, and steroidal anti-inflammatory agents such ashydrocortisone, hydrocortisone-21-monoesters (e.g.,hydrocortisone-21-acetate, hydrocortisone-21-butyrate,hydrocortisone-21-propionate, hydrocortisone-21-valerate, etc.),hydrocortisone-17,21-diesters (e.g., hydrocortisone-17,21-diacetate,hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21-dibutyrate,etc.), alclometasone, dexamethasone, flumethasone, prednisolone, andmethylprednisolone.

Anti-microbial agents useful in the dosage forms include by way ofexample tetracycline antibiotics and related compounds(chlortetracycline, oxytetracycline, demeclocycline, methacycline,doxycycline, minocycline, rolitetracycline); macrolide antibiotics suchas erythromycin, clarithromycin, and azithromycin; streptograminantibiotics such as quinupristin and dalfopristin; beta-lactamantibiotics, including penicillins (e.g., penicillin G, penicillin VK),antistaphylococcal penicillins (e.g., cloxacillin, dicloxacillin,nafcillin, and oxacillin), extended spectrum penicillins (e.g.,aminopenicillins such as ampicillin and amoxicillin, and theantipseudomonal penicillins such as carbenicillin), and cephalosporins(e.g., cefadroxil, cefepime, cephalexin, cefazolin, cefoxitin,cefotetan, cefuroxime, cefotaxime, ceftazidime, and ceftriaxone), andcarbapenems such as imipenem, meropenem and aztreonam; aminoglycosideantibiotics such as streptomycin, gentamicin, tobramycin, amikacin, andneomycin; glycopeptide antibiotics such as teicoplanin; sulfonamideantibiotics such as sulfacetamide, sulfabenzamide, sulfadiazine,sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, andsulfamethoxazole; quinolone antibiotics such as ciprofloxacin, nalidixicacid, and ofloxacin; anti-mycobacterials such as isoniazid, rifampin,rifabutin, ethambutol, pyrazinamide, ethionamide, aminosalicylic, andcycloserine; systemic antifungal agents such as itraconazole,ketoconazole, fluconazole, and amphotericin B; antiviral agents such asacyclovir, famcicylovir, ganciclovir, idoxuridine, sorivudine,trifluridine, valacyclovir, vidarabine, didanosine, stavudine,zalcitabine, zidovudine, amantadine, interferon alpha, ribavirin andrimantadine; and miscellaneous antimicrobial agents such aschloramphenicol, spectinomycin, polymyxin B (colistin), bacitracin,nitrofurantoin, methenamine mandelate and methenamine hippurate.

Anti-viral agents useful in the dosage forms include by way of examplethe antiherpes agents acyclovir, famciclovir, foscarnet, ganciclovir,idoxuridine, sorivudine, trifluridine, valacyclovir, and vidarabine; theantiretroviral agents didanosine, stavudine, zalcitabine, andzidovudine; and other antiviral agents such as amantadine, interferonalpha, ribavirin and rimantadine.

Anxiolytics and tranquilizers useful in the dosage forms include by wayof example benzodiazepines (e.g., alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, triazolam), buspirone, chlordiazepoxide, and droperidol.

Cardiac agents, which can be used in combination with diuretics, usefulin the dosage forms include by way of example amiodarone, amlodipine,atenolol, bepridil, bisoprolol bretylium, captopril, carvedilol,diltiazem, disopyramide, dofetilide, enalaprilat, enalapril, encainide,esmolol, flecainide, fosinopril, ibutilide, inamrinone, irbesartan,lidocaine, lisinopril, losartan, metroprolol, nadolol, nicardipine,nifedipine, procainamide, propafenone, propranolol, quinapril,quinidine, ramipril, trandolapril, and verapamil.

Cardiovascular agents useful in the dosage forms include by way ofexample angiotensin converting enzyme (ACE) inhibitors, cardiacglycosides, calcium channel blockers, beta-blockers, antiarrhythmics,cardioprotective agents, and angiotensin II receptor blocking agents.Examples of the foregoing classes of drugs include the following: ACEinhibitors such as enalapril,1-carboxymethyl-3-1-carboxy-3-phenyl-(1S)-propylamino-2,3,4,5-tetrahydro-1H-(3S)-1-benzazepine-2-one,3-(5-amino-1-carboxy-1S-pentyl)amino-2,3,4,5-tetrahydro-2-oxo-3S-1H-1-benzazepine-1-aceticacid or3-(1-ethoxycarbonyl-3-phenyl-(1S)-propylamino)-2,3,4,5-tetrahydro-2-oxo-(3S)-benzazepine-1-aceticacid monohydrochloride; cardiac glycosides such as digoxin anddigitoxin; inotropes such as amrinone and milrinone; calcium channelblockers such as verapamil, nifedipine, nicardipene, felodipine,isradipine, nimodipine, bepridil, amlodipine and diltiazem;beta-blockers such as atenolol, metoprolol; pindolol, propafenone,propranolol, esmolol, sotalol, timolol, and acebutolol; antiarrhythmicssuch as moricizine, ibutilide, procainamide, quinidine, disopyramide,lidocaine, phenytoin, tocainide, mexiletine, flecainide, encainide,bretylium and amiodarone; and cardioprotective agents such asdexrazoxane and leucovorin; vasodilators such as nitroglycerin; andangiotensin II receptor blocking agents such as losartan,hydrochlorothiazide, irbesartan, candesartan, telmisartan, eposartan,and valsartan.

CNS and respiratory stimulants useful in the dosage forms include by wayof example xanthines such as caffeine and theophylline; amphetaminessuch as amphetamine, benzphetamine hydrochloride, dextroamphetamine,dextroamphetamine sulfate, levamphetamine, levamphetamine hydrochloride,methamphetamine, and methamphetamine hydrochloride; and miscellaneousstimulants such as methylphenidate, methylphenidate hydrochloride,modafinil, pemoline, sibutramine, and sibutramine hydrochloride.

Hypnotic agents and sedatives useful in the dosage forms include by wayof example clomethiazole, ethinamate, etomidate, glutethimide,meprobamate, methyprylon, zolpidem, and barbiturates (e.g., amobarbital,apropbarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, thiopental).

Muscarinic receptor agonists and antagonists useful in the dosage formsinclude by way of example choline esters such as acetylcholine,methacholine, carbachol, bethanechol (carbamylmethylcholine),bethanechol chloride, cholinomimetic natural alkaloids and syntheticanalogs thereof, including pilocarpine, muscarine, McN-A-343, andoxotremorine. Muscarinic receptor antagonists are generally belladonnaalkaloids or semisynthetic or synthetic analogs thereof, such asatropine, scopolamine, homatropine, homatropine methyl bromide,ipratropium, methantheline, methscopolamine and tiotropium.

Neuroleptic agents useful in the dosage forms include by way of exampleantidepressant drugs, antimanic drugs, and antipsychotic agents, whereinantidepressant drugs include (a) the tricyclic antidepressants such asamoxapine, amitriptyline, clomipramine, desipramine, doxepin,imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine,(b) the serotonin reuptake inhibitors citalopram, fluoxetine,fluvoxamine, paroxetine, sertraline, and venlafaxine, (c) monoamineoxidase inhibitors such as phenelzine, tranylcypromine, and(−)-selegiline, and (d) other, “atypical” antidepressants such asnefazodone, trazodone and venlafaxine, and wherein antimanic andantipsychotic agents include (a) phenothiazines such as acetophenazine,acetophenazine maleate, chlorpromazine, chlorpromazine hydrochloride,fluphenazine, fluphenazine hydrochloride, fluphenazine enanthate,fluphenazine decanoate, mesoridazine, mesoridazine besylate,perphenazine, thioridazine, thioridazine hydrochloride, trifluoperazine,and trifluoperazine hydrochloride, (b) thioxanthenes such aschlorprothixene, thiothixene, and thiothixene hydrochloride, and (c)other heterocyclic drugs such as carbamazepine, clozapine, droperidol,haloperidol, haloperidol decanoate, loxapine succinate, molindone,molindone hydrochloride, olanzapine, pimozide, quetiapine, risperidone,and sertindole.

Peptide drugs useful in the dosage forms include by way of example thepeptidyl hormones activin, amylin, angiotensin, atrial natriureticpeptide (ANP), calcitonin, calcitonin gene-related peptide, calcitoninN-terminal flanking peptide, ciliary neurotrophic factor (CNTF),corticotropin (adrenocorticotropin hormone, ACTH),corticotropin-releasing factor (CRF or CRH), epidermal growth factor(EGF), follicle-stimulating hormone (FSH), gastrin, gastrin inhibitorypeptide (GIP), gastrin-releasing peptide, gonadotropin-releasing factor(GnRF or GNRH), growth hormone releasing factor (GRF, GRH), humanchorionic gonadotropin (hCH), inhibin A, inhibin B, insulin, luteinizinghormone (LH), luteinizing hormone-releasing hormone (LHRH),α-melanocyte-stimulating hormone, β-melanocyte-stimulating hormone,γ-melanocyte-stimulating hormone, melatonin, motilin, oxytocin(pitocin), pancreatic polypeptide, parathyroid hormone (PTH), placentallactogen, prolactin (PRL), prolactin-release inhibiting factor (PIF),prolactin-releasing factor (PRF), secretin, somatotropin (growthhormone, GH), somatostatin (SIF, growth hormone-release inhibitingfactor, GIF), thyrotropin (thyroid-stimulating hormone, TSH),thyrotropin-releasing factor (TRH or TRF), thyroxine, vasoactiveintestinal peptide (VIP), and vasopressin. Other peptidyl drugs are thecytokines, e.g., colony stimulating factor 4, heparin bindingneurotrophic factor (HBNF), interferon-α, interferon α-2a, interferonα-2b, interferon α-n3, interferon-β, etc., interleukin-1, interleukin-2,interleukin-3, interleukin-4, interleukin-5, interleukin-6, etc., tumornecrosis factor, tumor necrosis factor-α, granuloycte colony-stimulatingfactor (G-CSF), granulocyte-macrophage colony-stimulating factor(GM-CSF), macrophage colony-stimulating factor, midkine (MD), andthymopoietin. Still other peptidyl drugs that can be advantageouslydelivered using the present systems include endorphins (e.g.,dermorphin, dynorphin, α-endorphin, β-endorphin, γ-endorphin,α-endorphin, [Leu⁵]enkephalin, [Met⁵]enkephalin, substance P), kinins(e.g., bradykinin, potentiator B, bradykinin potentiator C, kallidin),LHRH analogues (e.g., buserelin, deslorelin, fertirelin, goserelin,histrelin, leuprolide, lutrelin, nafarelin, tryptorelin), and thecoagulation factors, such as α₁-antitrypsin, α₂-macroglobulin,antithrombin III, factor I (fibrinogen), factor II (prothrombin), factorIII (tissue prothrombin), factor V (proaccelerin), factor VII(proconvertin), factor VIII (antihemophilic globulin or AHG), factor IX(Christmas factor, plasma thromboplastin component or PTC), factor X(Stuart-Power factor), factor XI (plasma thromboplastin antecedent orPTA), factor XII (Hageman factor), heparin cofactor II, kallikrein,plasmin, plasminogen, prekallikrein, protein C, protein S, andthrombomodulin and combinations thereof.

Sex steroids useful in the dosage forms include by way of exampleprogestogens such as acetoxypregnenolone, allylestrenol, anagestoneacetate, chlormadinone acetate, cyproterone, cyproterone acetate,desogestrel, dihydrogesterone, dimethisterone, ethisterone(17α-ethinyltestosterone), ethynodiol diacetate, flurogestone acetate,gestadene, hydroxyprogesterone, hydroxyprogesterone acetate,hydroxyprogesterone caproate, hydroxymethyiprogesterone,hydroxymethyiprogesterone acetate, 3-ketodesogestrel, levonorgestrel,lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol,megestrol acetate, melengestrol acetate, norethindrone, norethindroneacetate, norethisterone, norethisterone acetate, norethynodrel,norgestimate, norgestrel, norgestrienone, normethisterone, andprogesterone. Also included within this general class are estrogens,e.g.: estradiol (i.e., 1,3,5-estratriene-3,17β-diol, or “17β-estradiol”)and its esters, including estradiol benzoate, valerate, cypionate,heptanoate, decanoate, acetate and diacetate; 17α-estradiol;ethinylestradiol (i.e., 17α-ethinylestradiol) and esters and ethersthereof, including ethinylestradiol 3-acetate and ethinylestradiol3-benzoate; estriol and estriol succinate; polyestrol phosphate; estroneand its esters and derivatives, including estrone acetate, estronesulfate, and piperazine estrone sulfate; quinestrol; mestranol; andconjugated equine estrogens. Androgenic agents, also included within thegeneral class of sex steroids, are drugs such as the naturally occurringandrogens androsterone, androsterone acetate, androsterone propionate,androsterone benzoate, androstenediol, androstenediol-3-acetate,androstenediol-17-acetate, androstenediol-3,17-diacetate,androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,androstenedione, dehydroepiandrosterone (DHEA; also termed“prasterone”), sodium dehydroepiandrosterone sulfate,4-dihydrotestosterone (DHT; also termed “stanolone”),5α-dihydrotestosterone, dromostanolone, dromostanolone propionate,ethylestrenol, nandrolone phenpropionate, nandrolone decanoate,nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolonebenzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol andtestosterone; pharmaceutically acceptable esters of testosterone and4-dihydrotestosterone, typically esters formed from the hydroxyl grouppresent at the C-17 position, including, but not limited to, theenanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate,buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprateesters; and pharmaceutically acceptable derivatives of testosterone suchas methyl testosterone, testolactone, oxymetholone and fluoxymesterone.

Where appropriate, any of the active agents described herein may beadministered in the form of a salt, ester, amide, prodrug, conjugate,active metabolite, isomer, fragment, analog, or the like, provided thatthe salt, ester, amide, prodrug, conjugate, active metabolite, isomer,fragment, or analog is pharmaceutically acceptable and pharmacologicallyactive in the present context. Salts, esters, amides, prodrugs,conjugates, active metabolites, isomers, fragments, and analogs of theagents may be prepared using standard procedures known to those skilledin the art of synthetic organic chemistry and described, for example, byJ. March, Advanced Organic Chemistry: Reactions, Mechanisms andStructure, 5th Edition (New York: Wiley-Interscience, 2001). Forexample, where appropriate, any of the compounds described herein may bein the form of a prodrug. The prodrug requires conversion to the activeagent.

Where appropriate, any of the compounds described herein may be in theform of a pharmaceutically acceptable salt. A pharmaceuticallyacceptable salt may be prepared from any pharmaceutically acceptableorganic acid or base, any pharmaceutically acceptable inorganic acid orbase, or combinations thereof. The acid or base used to prepare the saltmay be naturally occurring.

Suitable organic acids for preparing acid addition salts include, e.g.,C₁-C₆ alkyl and C₆-C₁₂ aryl carboxylic acids, di-carboxylic acids, andtri-carboxylic acids such as acetic acid, propionic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, glycolic acid, citric acid,pyruvic acid, oxalic acid, malic acid, malonic acid, benzoic acid,cinnamic acid, mandelic acid, salicylic acid, phthalic acid, andterephthalic acid, and aryl and alkyl sulfonic acids such asmethanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid,and the like. Suitable inorganic acids for preparing acid addition saltsinclude, e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, nitric acid, and phosphoric acid, and the like. An acidaddition salt may be reconverted to the free base by treatment with asuitable base.

Suitable organic bases for preparing basic addition salts include, e.g.,primary, secondary and tertiary amines, such as trimethylamine,triethylamine, tripropylamine, N,N-dibenzylethylenediamine,2-dimethylaminoethanol, ethanolamine, ethylenediamine, glutamine,glucosamine, histidine, and polyamine resins, cyclic amines such ascaffeine, N-ethylmorpholine, N-ethylpiperidine, and purine, and salts ofamines such as betaine, choline, and procaine, and the like. Suitableinorganic bases for preparing basic addition salts include, e.g., saltsderived from sodium, potassium, ammonium, calcium, ferric, ferrous,aluminum, lithium, magnesium, or zinc such as sodium hydroxide,potassium hydroxide, calcium carbonate, sodium carbonate, and potassiumcarbonate, and the like. A basic addition salt may be reconverted to thefree acid by treatment with a suitable acid.

Other derivatives and analogs of the active agents may be prepared usingstandard techniques known to those skilled in the art of syntheticorganic chemistry, or may be deduced by reference to the pertinentliterature. In addition, chiral active agents may be in isomericallypure form, or they may be administered as a racemic mixture of isomers.

Any of the compounds described herein may be the active agent in aformulation as described herein. Formulations may include one, two,three, or more than three of the active agents and drugs describedherein, and may also include one or more active agents not specificallyrecited herein.

When a dosage form or method is used or practiced in combination withthe administration of another agent, such as secondary analgesics,anticonvulsant agents, antidepressants, and the like, the additionalagent may be obtained from a commercial source in a variety of dosageforms (e.g., tablets, capsules, oral suspensions, and syrups). Theadditional agent may be administered as a separate dosage form or agastric retentive dosage form of the present invention may comprisingthe additional agent may be used.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

EXAMPLES

The following examples illustrate certain aspects and advantages of thepresent invention, however, the present invention is in no wayconsidered to be limited to the particular embodiments described below.

Example 1 Formulation of LC4SL (L4-4) Tablets

A gastric-retentive dosage form, referred to as LC4SL, was formulated asa single layer tablet to provide sustained release of levodopa andcarbidopa into the stomach over a period of approximately four hours.The dosage form having 200 mg levodopa and 54 mg carbidopa had a totalweight of 700 mg. The tablet contained 25 wt % POLYOX™1105 (with amolecular weight of approximately 900,000) and approximately 27 wt %microcrystalline cellulose. A high shear granulation of the levodopa andcarbidopa were dry blended with the excipients which are listed in Table1 below. Tablets were then manufactured using a Carver Press with a0.3937″×0.6299″ MOD OVAL die.

TABLE 1 % of Active Ingredients Layer mg/tablet Levodopa, USP 28.57200.0 Carbidopa, USP 7.71 54.0 Povidone, USP [Plasdone K-29/32] 1.09 7.6Avicel ® Microcrystalline Cellulose NF 26.63 186.4 Ph. Eur. JPPolyethylene Oxide NF [SENTRY ™ 25.00 175.0 POLYOX ™ 1105 LEO NF GradeMannitol, USP (Pearlitol 200 SD) 10.00 70.0 Magnesium Stearate NF,Non-Bovine 1.00 7.0 Total 100.00 700.0

Example 2 Formulation of the LC6SL (L4-6) Tablets

The L4-6 gastric-retentive dosage form was formulated as a single layertablet to provide sustained release of levodopa and carbidopa into thestomach over a period of approximately six hours. The dosage form having200 mg levodopa and 54 mg carbidopa had a total weight of 700 mg. Thetablet contained approximately 61.6 wt % POLYOX™1105 (with a molecularweight of approximately 900,000). A high shear granulation of thelevodopa and carbidopa were dry blended with the excipients, detailed inTable 2 below. Tablets were then manufactured using a Carver Press witha 0.3937″×0.6299″ MOD OVAL die.

TABLE 2 Ingredients % of Active Layer mg/tablet Levodopa, USP 28.57200.0 Carbidopa, USP 7.71 54.0 Povidone, USP [Plasdone K-29/32] 1.09 7.6Polyethylene Oxide NF [SENTRY ™ 61.63 431.4 POLYOX ™ 1105 LEO NF GradeMagnesium Stearate NF, Non-Bovine 1.00 7.0 Total 100.00 700.0

Example 3 Formulation of the LC6BL (L4-6 Bi-Layer) Bilayer Tablets

The L4-6 Bilayer gastric-retentive dosage form was formulated as abilayer tablet to provide sustained release of levodopa and carbidopainto the stomach over a period of approximately six hours. The full doseof levodopa (200 mg) and carbidopa (54 mg) is present in the first layerwhich contains about 46.7 wt % Polyox 1105. The tablet containedapproximately 61.6 wt % POLYOX™1105 (with a molecular weight ofapproximately 900,000). A high shear granulation of the levodopa andcarbidopa were dry blended with the excipients. The components for theactive layer of this bilayer tablet are listed in Table 3 below. Thesecond layer (swelling layer) contained 98.5 wt % POLYOX™ WSR-303 as aswellable gastric retentive layer to further promote retention of thedosage form in the stomach. In the formulation described herein, POLYOX™WSR-303 TG was used in the second layer, however, POLYOX™ WSR-303 FP mayalso be used. The bilayer dosage form had a total weight of 700 mg. Theingredients for the swelling layer are listed below in Table 4. Tabletswere manufactured using a Carver Press with a 0.3937″×0.6299″ MOD OVALdie.

TABLE 3 Ingredients (Active Layer) % of Active Layer mg/tablet Levodopa,USP 40.00 200.0 Carbidopa, USP 10.80 54.0 Povidone, USP [PlasdoneK-29/32] 1.52 7.6 Polyethylene Oxide NF [SENTRY ™ 46.68 233.4 POLYOX ™1105 LEO NF Grade Magnesium Stearate NF, Non-Bovine 1.00 5.0 Total100.00 500.0

TABLE 4 Ingredients (Swelling Layer) % of Active Layer mg/tabletPolyethylene Oxide NF [SENTRY ™ 98.50 295.5 POLYOX ™ 1105 LEO NF GradeOpadry, Blue [YS-1-10699] 1.00 3.0 Magnesium Stearate NF, Non-Bovine 0.51.5 Total 100.00 300.0

Example 4 In-Vitro Dissolution Release Profiles

In vitro dissolution release profiles of levodopa and carbidopa releasefrom the LC4SL, LC6SL and LC6BL tablets manufactured as described abovewere determined using a USP Dissolution Apparatus III (Vankel Bio-Dis,Varian, Cary, N.C.) containing a dissolution medium of 250 ml 0.1N HClper vessel at 37.0±0.5° C. Samples were taken without media replacementat 1, 2, 3, 4, 5 and 6 hours. The dissolution samples from the statedtime-points were analyzed for levodopa and carbidopa, respectively byHPLC using a C18 HPLC column (4.6 mm×15 cm, 5 μm particle size fromThermo Scientific) with column temperature at 25° C., flow rate of 1.0ml per minute, at a detection wavelength of 280 nm. Results for levodoparelease are shown in FIG. 1. Results for carbidopa release are presentedin FIG. 2.

Example 5 In-Vitro Dissolution Comparison

Dissolution testing was also performed to compare release profiles fromthe gastric retentive dosage forms formulated as described herein withthe release profiles of levodopa/carbidopa sustained release tabletscurrently available on the market. Specifically, SINEMET® CR tabletsmanufactured by Merck & Co. (Whitehouse Station, N.J.), Inc., andlevodopa/carbidopa tablets manufactured by Mylan Pharmaceuticals, Inc(Morgantown, W. Va.). Testing was done using a USP Dissolution ApparatusIII (Vankel Bio-Dis, Varian, Cary, N.C.) containing a dissolution mediumof 250 ml 0.1N HCl per vessel at temperature of 37.0±0.5° C. withreciprocating speed of 30 dips per minute. The dissolution samplingtime-points were: 0.08, 0.25, 0.5, 1, 2.5, and 4 hours for Tablets fromMylan and Merck; 0.5, 1, 2, 3, and 4 hours for LC4SL tablets; 1, 2, 3,4, and 5 hours for the LC6SL tablets; and 1, 2, 3, 5, and 7 hours forthe LC6BL tablets. The dissolution samples from the stated time-pointswere analyzed for levodopa and carbidopa, respectively by HPLC using aC18 HPLC column (4.6 mm×15 cm, 5 μm particle size from ThermoScientific) with column temperature at 25° C., flow rate of 1.0 ml perminute, at a detection wavelength of 280 nm.

Results of the dissolution testing are presented below in Table 5 andgraphically represented in FIG. 3. Values in Table 5 represent theamount of levodopa released from each dosage form at the specified timeperiod in terms of percent of the label claim (% LC).

TABLE 5 % Label Claim for Levodopa Time (h) Mylan Sinemet LC4SL LC6SLLC6BL 0.08 11.46 20.05 — — — 0.25 34.28 56.96 — — — 0.50 63.01 93.5020.24 — — 1.00 98.79 102.79 38.26 24.43 29.78 2.00 — — 67.82 44.50 51.552.50 104.85 102.50 — — — 3.00 — — 88.43 64.73 63.05 4.00 104.52 102.0599.53 83.84 — 5.00 — — — 98.21 78.01 7.00 — — — — 95.18

Example 6 Erosion and Pharmacokinetic Studies in Dogs

A four-way randomized study was performed in dogs to evaluate therelative bioavailability and pharmacokinetics of levodopa following oraladministration of gastric retentive (GR) controlled-release dosage formsof levodopa/carbidopa (LC4SL, LC6SL and LC6BL) as compared to themarketed controlled-release levodopa/carbidopa formulations (Sinemet®CR) manufactured by Merck & Co., Inc. and Mylan Pharmaceuticals, Inc.The study utilized beagle dogs.

This randomized 4-way crossover study was carried out using five healthyfemale beagle dogs, each weighing 12-16 kg. Following an overnight fastof at least 14 hr the animals were administered 200 mg carbidopa.Forty-five minutes later they were fed 100 gm of canned dog food(Pedigree Traditional Ground Dinner with Chunky Chicken) andadministered a single oral dosage of a LC4SL, LC6SL or LC6BL tabletcontaining 200 mg levodopa and 50 mg carbidopa, or a marketedextended-release formulation containing 200 mg levodopa/50 mg carbidopa(Sinemet® CR). The treatments were administered within 15 minutes of theanimals consuming the meal. There was at least one week betweenadministrations to allow for recovery from blood sampling and washout.

The LC4SL, LC6SL and LC6BL tablets were manufactured according to themethods described in Examples 1-3, with the exception that radio-opaquestrings were placed in the center of the tablets in the shape of an “X”to act as a marker for gastrointestinal transit and erosion of thetablet. The tablets were tested in vitro to determine their release rateusing an USP Dissolution Apparatus III and compared to that of SinemetCR.

A randomized schedule was employed to administer four different dosageforms containing 200 mg levodopa and 50 mg carbidopa to the dogs. Dosageform A was SINEMET® CR, manufactured by Merck & Co., Inc. Dosage Form Bwas the LC4SL tablet, Dosage Form C was the LC6SL tablet and Dosage FormD was the LC6BL bilayer tablet.

The randomization schedule is described in Table 6 below. Each periodrepresents one week. Each dog received each of the Dosage Forms A-D,being administered one of the dosage forms at the beginning of a oneweek period.

TABLE 6 Dog # Period 1 Period 2 Period 3 Period 4 1 A D C B 2 D C B A 3C D A B 4 B A D C 5 A B C D

Erosion of the GR dosage forms was monitored by fluoroscopy with imagesobtained every 30 minutes until the tablet completely disintegrated.Physical separation of the strings was considered to representing thetime of complete disintegration of the tablets.

Individual and mean tablet erosion times are presented in Table 7. Alsopresented in Table 7 is the predicted human erosion time for comparison.Predicted human erosion time is based on previous studies of GRformulations where both dog and human erosion studies were conducted onthe same formulation. These studies resulted in determination of themathematical relationship, HE=DE×1.5+1.3, where HE is human erosion timeand DE is dog erosion time.

The in vivo erosion studies indicate that the LC4SL formulations willhave a levodopa delivery time of approximately 6-7 hours in humans andthe LC6SL 6 hour formulation will have a delivery time of about 10hours.

TABLE 7 Mean ± Predicted Tablet Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 SD HumanLC4SL 3.75 3.75 3.25 4.75 3.25 3.75 ± 0.61 6.93 ± 1.06 LC6SL 6.75 5.756.75 3.75 7.75 6.15 ± 1.52 10.53 ± 2.27  LC6BL 5.25 5.25 6.25 4.75 6.255.55 ± 0.67 9.63 ± 1.01

To measure levels of levodopa and carbidopa in the plasma afteradministration of the tablets, 3 ml blood samples were collected in 5 mlVacutainer® (BD) tubes containing 0.057 ml of 15% (K3) EDTA(anticoagulant) for determination of levodopa concentrations in plasma.Samples were drawn via venipuncture from the cephalic veins at 0.5 h,1.0 h, 2.0 h, 3.0 h, 4.0 h, 5.0 h, 6.0 h, 7.0 h, 8.0 h, 10.0 h, and 12.0h after dosing.

Immediately after collection the tube was gently inverted several timesto mix the anticoagulant with the blood sample. The samples were thencentrifuged at 4-8° C. for 10 minutes at 1,500 rpm. Then 1 ml of theplasma fraction was pipetted into polypropylene cryo-tubes containing 5mg sodium metabisulfite (stabilizing agent) and mixed thoroughly andthen immediately frozen at −80° C. All sample collection and cryo-tubeswere labeled to identify the subject, study date, time point, andperiod.

All plasma samples were stored frozen at −80° C. until shipment. Priorto shipping, the samples were packed into thermal insulated containerswith sufficient dry ice to assure they remain frozen during shipment (atleast 72 hr). Samples were shipped by overnight, priority courier toBASi (West Lafayette, Ind.).

Levodopa was extracted from dog plasma by an automated solid phasealumina extraction procedure. Before the extraction, N-methyldopaminehydrochloride was added as an internal standard. The extract wasinjected into an HPLC system with electrochemical detection using anLC-18-DB ODS column with an ion-pairing reagent phosphate bufferedmobile phase. The concentration range of the method was 10 ng/ml to2,000 ng/ml.

Non-compartmental calculations using the linear trapezoidal rule wereused to determine the area under the curve from 0 to 12 hours (AUC₀₋₁₂),while the maximum concentration (C_(max)) and time to maximumconcentration (t_(max)) were determined by inspection of the data.Relative bioavailability of the GR formulations to the comparator wascalculated by dividing the AUC₀₋₁₂ of the GR tablets by the comparator'sAUC₀₋₁₂. In addition, the time the plasma concentration was equal to orgreater than 1500 ng/ml was determined for the GR tablets and comparedto Sinemet CR. Values below the limit of quantitation for the assay wereassumed to be zero for purposes of calculation.

All data presented herein are expressed as either the mean±standarddeviation or as the median. One-way ANOVA with repeat measures was usedto determine whether there was a difference between mean values. When adifference was found, the Dunnett's test was used to determine which GRformulation means were different from Sinemet CR for PK data. Likewisein the erosion studies the 6 hr formulations were compared to the 4 hrformulation using the Dunnett's test. A p-value of ≦0.05 was consideredto indicate a significant difference.

Release profiles as determined by in vitro dissolution testing of thethree GR formulations in comparison to Sinemet CR are illustrated inFIG. 4. Under the test conditions Sinemet CR (S-CR) completely releasedlevodopa within one hour. In comparison the SL-4H GR tablets (SL-4HR)had nearly linear release of levodopa though 4 hour and the SL-6H GRtablets (SL-6 HR) had a linear release through 5 hour. The BL-6H GRtablets (BL-6H) had a somewhat faster release of levodopa in the earlytime points and then the release slowed at later time points resultingin complete release in 6-7 hours.

Individual and mean pharmacokinetic parameters for each formulation arelisted in Tables 8-11 below, as well as the relative bioavailability forthe GR tablets (Table 12). The mean levodopa plasma concentration timeprofile is illustrated in FIG. 5 and the individual profiles arepresented in FIGS. 6A-E. The concentration time profiles of the threedosage forms were typical of an extended-release formulation (FIGS.3-7). In comparison to Sinemet CR, the AUC of all extended-release GRtablets were significantly higher (Table 8, * indicates where p<0.05compared to Sinemet CR). C_(max) and t_(max) values were not differentfrom S-CR for the extended-release OR tablets (Tables 9 and 10,respectively 1, p>0.05). However, there was a statistically significantincrease in the duration of time the plasma concentration of levodopawas great than 15 ng/ml (Table 11). CV is the coefficient of variation.

TABLE 8 AUC₀₋₁₂ (ng · h/ml) Tablet Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 Mean ±SD CV (%) S-CR 8662 10554 11295 11531 5825 9573 ± 2379 24.9 LC6BL 1512011350 15655 17971 14697 14959 ± 2381* 15.9 LC6SL 13613 11297 15125 1655617379 14794 ± 2425* 16.4 LC4SL 12015 12696 13632 14045 12896 13057 ±798*  6.1

TABLE 9 C_(max) (ng/ml) Mean ± Tablet Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 SDCV (%) S-CR 2801 3000 3043 3367 2969 3036 ± 206 6.8 LC6BL 2915 2603 29703101 2582 2834 ± 231 8.2 LC6SL 2840 2729 2912 2914 3271 2984 ± 308 5.5LC4SL 3037 2494 3204 2912 3271 2984 ± 308 10.3

TABLE 10 t_(max) Mean ± Tablet Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 SD S-CR 2 32 2 1 2.0 ± 0.7 LC6BL 2 3 2 4 2 2.6 ± 0.9 LC6SL 4 4 3 3 2 3.2 ± 0.8LC4SL 2 4 2 3 3 2.8 ± 0.8

TABLE 11 Duration the plasma concentration of levodopa greater than 15ng/ml (h) Mean ± Tablet Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 SD CV (%) S-CR2.88 3.26 3.69 3.46 1.70 3.00 ± 0.78  26.0 LC6BL 5.26 4.17 4.89 5.045.15 4.90 ± 0.43* 8.8 LC6SL 4.79 3.97 5.54 6.02 4.98 5.06 ± 0.78* 15.4LC4SL 4.21 4.69 4.69 6.16 4.12 4.77 ± 0.82* 17.2

TABLE 12 % Relative Bioavailability (BA) Dog Dog Mean ± Tablet Dog 1 2Dog 3 4 Dog 5 SD CV (%) LC6BL 175 108 139 156 252 166 ± 54 32.5 LC6SL157 107 134 144 298 168 ± 75 44.6 LC4SL 139 120 121 122 221 145 ± 4430.3

The concentration time profiles for the levodopa extended-release GRtablets demonstrate a sustained-release profile compared to theextended-release comparator (Sinemet CR). In addition, the relativebioavailability compared to Sinemet CR was significantly increased,while the C_(max) and t_(max) values were not different. Although thet_(max) values were not as different as might be expected with a longerrelease profile, the time the levodopa concentration was greater than1500 ng/ml was significantly increased. This indicates the plateau wasmaintained for a significantly longer period and may result in moreconstant levodopa blood levels at steady state.

The PK profiles of the levodopa extended-release GR tablets also tendedto follow the in vitro release profiles. The LC4SL (SL-4H) tabletdemonstrated a rapid rise to C_(max) which is consistent with thequicker in vitro release. The LC6BL (BL-6H) tablet also demonstrated amore rapid rise to C_(max) than the LC6SL (SL-6H), which is alsoconsistent with their in vitro release profiles. In vitro the LC6BLtablet demonstrated a more rapid release at early time point and thenslowed its release while the LC6SL tablet demonstrated a near linearrelease over time and thus lower levodopa blood concentration at earlytime point in the concentration time profiles.

The in vivo erosion studies indicate that the LC4SL 4-hour formulationwill have a levodopa delivery time of approximately 6-7 hours in humansand the LC6SL 6-hour formulation will have a delivery time of about 10hours. PK modeling data has indicated that a predicted release time of7-10 hours may result in twice a day dosing in humans with a relativelyconstant levodopa blood concentration.

In conclusion, all GR extended formulations extended the release andincreased the bioavailability of levodopa compared to SINEMET® CR inBeagle dogs.

Example 7 Phase I Pharmacokinetics Study

An open label, three-way crossover study was done to analyzelevodopa/carbidopa tolerability and pharmacokinetics followingadministration of two Gastric Retentive (GR®) extended release tabletsformulated as described herein as compared to administration of areference extended release tablet currently marketed for treatment ofpatients with Parkinson's Disease.

The objective of this study was to compare the pharmacokinetic profilesof levodopa and carbidopa delivered from two gastric retentive testformulations of levodopa/carbidopa ER tablets, LC4SL and LC6BL, withfrom a comparator carbidopa/levodopa extended-release tablet.Parkinson's Disease patients were administered the dosage forms underfed conditions.

This was a randomized, open-label, single-dose, six-sequence,three-treatment, three-period crossover designed in Parkinson's Diseasepatients. Eighteen men (7) and women (11) at least 30 years of age witha diagnosis of idiopathic Parkinson's disease with stable disease and amodified Hoehn & Yahr stage equal to or less than 3 (Stage 1 unilateraldisease, stage 2 mild bilateral disease and stage 3 more advancedbilateral disease) were enrolled. Fifteen minutes after the start of astandardized, approximately 750 calorie (˜40% of calories from fat) mealthe subjects were administered one of the following test formulations:

Formulation 1: A single layer gastric retentive Levodopa 200mg/Carbidopa 50 mg Extended Release Tablet with a in vitro release timeof 4 hr (LC4SL); Formulation 2: A bilayer layer gastric retentiveLevodopa 200 mg/Carbidopa 50 mg Extended Release Tablet with a in vitrorelease time of 6 hr (LC6BL); Comparator: A commercially availableCarbidopa and Levodopa Extended-release Tablet, containing 200 mglevodopa and 50 mg carbidopa (Mylan).

Blood samples were taken prior to administration and at 0.5, 1.0, 1.5,2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hoursafter oral drug administration. The plasma concentrations of levodopaand carbidopa were analyzed using a validated assay method. There wereat least 7 but no more than 14 days between treatment administrations.

Pharmacokinetic analysis employing non-compartmental methods was used todetermine the following parameters for levodopa and carbidopa: areaunder the curve from dose administration to last time point (AUC_(0-t)),AUC for dose administration to infinity (AUC_(0-∞)), maximumconcentration (C_(max)), time to maximum concentration (t_(max)), andthe terminal half-life (t_(1/2)).

Mean levodopa and carbidopa pharmacokinetic parameters for eachformulation are listed in Tables 13 and 14, respectively. The meanlevodopa and carbidopa plasma concentration time profiles areillustrated in FIGS. 7A and 7B, respectively. The gastric retentiveformulations exhibited an typical extended-release profile with areduced C_(max) and an extended t_(max) for levodopa compared to thefaster releasing comparator formulation. Specifically, results show thatthe LC4SL extended the median time point at which levodopa blood levelsexceeded the efficacious threshold of 300 ng/ml to approximately ninehours, compared to approximately seven hours for the generic (Mylan)version of SINEMET4 CR. The tiem to medidan peak levodopa blood levelsin the study was extended to about 4 hours, compared to 2.8 hours forthe comparator. Moreover, the bioavailability of levodopa for the singlelayer 4 hour release formulation relative to the comparator formulationcalculated as the ratio of AUC_(inf) for individual subjects is 96±12%.This value is 75±24% for the bilayer 6 hour release formulation.

TABLE 13 Formulation 1 Formulation 2 Formulation Comparator (LC4SL)(LC6BL) t_(max) (h) 3 (1.5-4) 4 (2-6) 4.0 (1.5-1.0) mean (SD) C_(max)(ng/ml) 1659 ± 544  1306 ± 496  858 ± 392 CV = 32.7% CV = 37.9% CV =45.7% AUC_(0-t) (ng · h/ml) 5806 ± 1967 5107 ± 1318 4265 ± 1876 CV =33.8% CV = 25.8% CV = 44.0% AUC_(0-∞) (ng · h/ml) 5852 ± 1968 5150 ±1319 4427 ± 1941 CV = 33.6% CV = 25.6% CV = 43.8% t_(1/2) (h) 1.7 ± 0.61.5 ± 0.2 2.3 ± 2.0

TABLE 14 Formulation 1 Formulation 2 Formulation Comparator (LC4SL)(LC6BL) t_(max) (h) 4 (2-8) 5 (3-8) 5 (2-16) mean (SD) C_(max) (ng/ml)114 ± 43  115 ± 66  71 ± 44 CV = 32.7% CV = 57.3% CV = 57.1% AUC_(0-t)(ng · h/ml) 668 ± 247 615 ± 238 475 ± 266 CV = 37.0% CV = 38.7% CV =56.0% AUC_(0-∞) (ng · h/ml) 677 ± 247 622 ± 240 482 ± 267 CV = 36.5% CV= 38.6% CV = 55.4% t_(1/2) (h) 3.8 ± 1.1 3.4 ± 0.7 3.4 ± 0.7

Example 8 In Vitro-In Vivo Drug Release Correlation

As erosion of tablet matrix is the mechanism for drug release from thethree formulations described herein (LC4SL, LC6SL and LC6BL), and thehydrodynamic condition (degree of agitation) of the surrounding fluidenvironment of the tablet influences this erosion, drug release in vitrodetermined by dissolution testing was evaluated under variousdissolution medium agitation conditions using three different USPapparatuses at various rotation speeds or oscillation rates: USPApparatus 1 (basket), 100 and 150 revolutions per minute (rpm); USPApparatus 2 (paddle), 100 and 150 rpm; and USP Apparatus 3(reciprocating cylinder) at 10, 20, and 30 cycles per minute (cpm). Inall cases, the dissolution medium is 0.1 N Hydrochloric acid (HCl),maintained at a temperature of 37±0.5° C. Cumulative drug release overtime, represented as percent of labeled claim (% LC) for drug content,is plotted as a function of dissolution medium sampling time.

In vivo drug release is represented by in vivo absorption as levodopaabsorption is relatively fast compared with drug release which extendsover a period of hours in these formulations. The in viva absorptiontime profile of levodopa for the three formulations were determined fromthe plasma concentration time profiles obtained from the clinicalpharmacokinetic study using the Wagner-Nelson method (Malcom Rowland,Thomas N. Tozer (Eds.) “Estimation of Adsorption Kinetics from PlasmaConcentration Data” in Clinical Pharmacokinetics, pp 480-483, Williams &Wilkins, 1995). Since the measure of cumulative absorption over timederived from this method is the percent of the total amount of drugeventually absorbed, this was multiplied by the bioavailability of thetest formulations relative to the comparator formulation (ratio ofAUC_(Inf)) as an indication of the actual amount of drug absorbed.

The in vitro drug release profiles and the in vivo absorption profilesare plotted together as a function of time for each formulation (FIGS.8A, B, and C, respectively). As can be seen from the above figures, invitro release is higher than in viva at a given time and is higher forhigher degrees of medium agitation. However, for Formulation 01 and 03(LC4SL and LC6BL, respectively) in vitro release profiles obtained fromUSP Apparatus 1 and 2 at 150 rpm, and USP Apparatus 3 at 10 cpm) havevery similar slopes compared to the in vivo absorption profiles. This ismore apparent if the in vitro profiles are shifted to the right by 1hour (FIGS. 8D and 8E), which then almost coincide with the in vivoabsorption profiles. As for the comparator formulation, this is case forUSP Apparatus 1 and 2 at 100 and 200 rpm and is more apparent with atime shift of 1 hr for 150 rpm profiles and a time shift of 0.5 hr for100 rpm profiles. These time shifts between in vitro and in vivoprofiles seems to be the presence of a time lag in the in vivoabsorption profiles.

Example 9 Pharmacokinetic Simulation of Extended Release Levodopa

Pharmacokinetic simulation analysis was performed to predictpharmacokinetic values based on data from the Phase I trial described inExample 7. The data from the Phase I trial were used to calculate thepeak and 12-hour post-administration levodopa plasma concentration, aswell as the ratio of the mean C_(max) to the mean C₁₂ (plasmaconcentration of levodopa 12 hours after administration) and the meanratio of C_(max) to C₁₂. It can be see from Table 15 that the ratio ofC_(max) to C₁₂ for the LC4SL formulation is ˜50% of that of thecomparator. This indicates the likelihood that the fluctuation in plasmaconcentration at steady state under the same twice daily dosing regimenwill be less than that of the comparator by the same magnitude.

TABLE 15 Mean peak Plasma Mean Ratio of Mean Ratio* Conc. Plasma MeanCmax/C12 h ± (Cmax, Conc. At 12 h Cmax to SD ng/ml) (C12 h, ng/ml) MeanC₁₂ (CV %) LC4SL 1306 53 25 27 ± 16 (60) LC6BL 858 121 7 15 ± 15 (99)Comparator 1659 29 57 66 ± 21 (32) *Individual subjects

The average plasma concentration profiles were fitted to aone-compartment pharmacokinetic model with zero order input and firstorder elimination for the Comparator and the LC4SL formulation. Zeroorder release time, apparent volume of distribution, and eliminationconstants were obtained as fitted parameters and are presented in Table3.

TABLE 3 Parameter Comparator LC4SL Formulation Zero Order Release Time(h) 3.3 6.2 Apparent Volume of 79500 77300 Distribution (ml) EliminationRate Constant (h⁻¹) 0.429 0.469 Elimantion Half-life (h) 1.62 1.48

Using these parameters and the method of superposition (Gibaldi &Perrier, 1982, Pharmacokinetics, New York: Dekker), average, peak, andtrough plasma concentrations at steady state under twice daily or threetimes daily administrations were predicted for these formulations, andare presented in Table 4.

TABLE 4 Comparator LC4SL Theoretical Total Daily 200 × 2 200 × 3 400 × 3200 × 2 200 × 3 600 × 2 600 × 2 600 × 2 Dose Individual 200 200 400 200200 600 600 600 Dose (mg) Zero Order 3.3 3.3 3.3 6.2 6.2 6.2 8 9 ReleaseTime (h) Zero Order 60.6 60.6 121 32.3 32.3 96.8 75.0 73.3 Release Rate(mg/h) Dosing 12 8 8 12 8 12 12 12 Interval (h) Peak Plasma 1354 13912781 844 861 2533 2027 1818 Conc. At Steady state C_(ss,max) (ng/ml)Trough 32 185 370 56 370 167 311 445 Plasma Conc. At Steady stateC_(ss,min) (ng/ml) Ratio C_(ss,max)/ 41.8 7.5 7.5 15.2 2.3 15.2 6.5 4.1C_(ss,min) Steady state 489 733 1466 460 690 1379 1379 1379 AveragePlasma Conc. C_(ss,avg) (ng/ml) Fluctuation 270 164 164 172 71 172 124100 (%)* Swing (%)** 4078 651 651 1418 133 1418 553 308 *Fluctuation (%)= (C_(ss,max) − C_(ss,min))/C_(ss,avg) × 100 **Swing (%) = (C_(ss,max) −C_(ss,min))/C_(ss,min) × 100

Under the same dosing regimen, the simulations show that twice daily(every 12 hours) or three times daily administration (every 8 hours),the LC4SL dosage form has much less fluctuation in plasma concentrationover a dosing interval compared to the comparator (172% vs. 270% and 71%vs. 164%), lower C_(max) and higher C_(min), hence a lower ratio, andless swing also. However, when the LC6BL formulation administered twicedaily is compared to the Comparator administered three times daily, thetrough plasma concentration will be lower despite similar peak andaverage concentrations and fluctuation (Table 4). Two theoreticalformulation cases were also simulated where the zero order release timeis extended to 8 and 9 hours for the LC4SL formulation when administeredtwice daily, with all other parameters being the same. Under theseconditions, the LC4SL formulation will have lower peak to trough ratiosand fluctuations compared to the Comparator dosed twice daily. Thetrough concentration for the 8 hr theoretical formulation is somewhatlower (16%) than that of the comparator (311 vs. 370 ng/ml), while thatof the 9 hr theoretical formulation is higher (445 ng/ml).

The invention claimed is:
 1. A method for treating a subject suffering from a movement disorder, comprising orally administering to said subject an extended release dosage form comprising a polymer matrix, wherein the polymer matrix comprises at least one hydrophilic polymer wherein the at least one hydrophilic polymer is present in the polymer matrix in an amount ranging from 20 wt % to 60 wt % and the at least one hydrophilic polymer comprises polyethylene oxide) having a molecular weight of about 900,000 Daltons to 2,000,000 Daltons, wherein a first dose of levodopa and a first dose of carbidopa are dispersed in the polymer matrix, and wherein the polymer matrix swells upon imbibition of fluid to a size sufficient for gastric retention in the gastrointestinal tract of the subject in a fed mode, wherein not more than 40% of the first dose of levodopa and not more than 40% of the first dose of carbidopa are released from the dosage form within about the first hour after administration, and wherein at least 80% of the first dose of levodopa and at least 80% of the first dose of carbidopa are released from the dosage form during a period of about 8 hours after oral administration.
 2. The method of claim 1, wherein said administering comprises administering the dosage form twice in a 24-hour period, and wherein said administering is with a meal.
 3. The method of claim 1, wherein the movement disorder is selected from the group consisting of Parkinson's Disease, Huntington's chorea, residual amblyopia, Angelman Syndrome, progressive supranuclear palsy, Wilson's disease, Tourette's syndrome, epilepsy, and dyskinesia.
 4. The method of claim 1, wherein the ratio of the first dose of levodopa to the first dose of carbidopa in the dosage form is between 10:1 and 1:1.
 5. The method of claim 1, wherein the dosage form further comprises an antioxidant.
 6. The method of claim 1, wherein the polymer matrix of the dosage form is comprised of a mixture of at least two hydrophilic polymers.
 7. The method of claim 1, wherein upon administration of the dosage form to the subject, the dosage form imbibes fluid and swells to a size between about 110% to 170% of the dosage form's size prior to administration within 1 hour after the administering.
 8. The method of claim 1, wherein between about 10% to about 40% of the levodopa is released from the dosage form within about 1 hour in an in vitro dissolution test.
 9. The method of claim 1, wherein the administering produces a plasma profile in the subject comprising: a prolonged plasma level of levodopa for at least 6-10 hours or 8-12 hours maintaining therapeutic efficacy; and the C_(max) for levodopa is between about 300 ng/ml to about 1500 ng/ml and a C_(min) for levodopa of between about 300 ng/ml to about 1500 ng/ml.
 10. The method of claim 9, wherein when administered to the subject the dosage form provides a ratio of C_(max) to C_(min) for levodopa less than or equal to about four.
 11. The method of claim 1, wherein the dosage form further comprises an immediate release portion comprising a second dose of levodopa and a second dose of the carbidopa, both of the second doses dispersed in the immediate release portion, said immediate release portion in contact with said polymer matrix.
 12. The method of claim 11, wherein the ratio of the second dose of levodopa to the second dose of carbidopa is between 10:1 and 1:1.
 13. The method of claim 11, wherein the dosage form is a bilayer tablet, wherein the immediate release portion is an immediate release layer and the polymer matrix is an extended release layer.
 14. The method of claim 11, wherein the administering produces a plasma profile in the subject comprising: a fast onset plasma level achieved within less than about two hours; followed by a prolonged plasma level of carbidopa for at least 6-10 hours or 8-12 hours maintaining therapeutic efficacy; and a C_(max) for levodopa of between about 300 ng/ml to about 1500 ng/ml of levodopa.
 15. The method of claim 11, wherein the ratio of the C_(max) to the C_(min) for levodopa is less than or equal to about five. 